EP2838900B1 - Composés et procédés pour un traitement antiviral - Google Patents
Composés et procédés pour un traitement antiviral Download PDFInfo
- Publication number
- EP2838900B1 EP2838900B1 EP13718996.5A EP13718996A EP2838900B1 EP 2838900 B1 EP2838900 B1 EP 2838900B1 EP 13718996 A EP13718996 A EP 13718996A EP 2838900 B1 EP2838900 B1 EP 2838900B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- heterocyclyl
- cycloalkyl
- aryl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000001875 compounds Chemical class 0.000 title claims description 412
- 238000000034 method Methods 0.000 title description 67
- 238000011282 treatment Methods 0.000 title description 24
- 230000000840 anti-viral effect Effects 0.000 title description 4
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 362
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 174
- 150000003839 salts Chemical class 0.000 claims description 154
- 239000000203 mixture Substances 0.000 claims description 143
- 229910052727 yttrium Inorganic materials 0.000 claims description 137
- 229910052757 nitrogen Inorganic materials 0.000 claims description 126
- 229910017711 NHRa Inorganic materials 0.000 claims description 101
- 125000003118 aryl group Chemical group 0.000 claims description 101
- -1 C2-C20 heterocyclyl Chemical group 0.000 claims description 96
- 229910052799 carbon Inorganic materials 0.000 claims description 85
- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims description 82
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 76
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 75
- 229910052736 halogen Inorganic materials 0.000 claims description 68
- 150000002367 halogens Chemical class 0.000 claims description 68
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 67
- 239000003814 drug Substances 0.000 claims description 50
- 125000004432 carbon atom Chemical group C* 0.000 claims description 48
- 150000001721 carbon Chemical group 0.000 claims description 36
- 125000000623 heterocyclic group Chemical group 0.000 claims description 33
- 229940124597 therapeutic agent Drugs 0.000 claims description 30
- 125000006648 (C1-C8) haloalkyl group Chemical group 0.000 claims description 29
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 29
- 241000711904 Pneumoviridae Species 0.000 claims description 24
- 125000004043 oxo group Chemical group O=* 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 16
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000002393 azetidinyl group Chemical group 0.000 claims description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 9
- 208000030925 respiratory syncytial virus infectious disease Diseases 0.000 claims description 9
- 230000001225 therapeutic effect Effects 0.000 claims description 9
- 230000009385 viral infection Effects 0.000 claims description 9
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 8
- 206010061603 Respiratory syncytial virus infection Diseases 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- MTPVBMVUENFFLL-HXUWFJFHSA-N 1-(2-fluorophenyl)-3-[(3s)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]urea Chemical compound FC1=CC=CC=C1NC(=O)N[C@@H]1C(=O)NC2=CC=CC=C2C(C=2C=CC=CC=2)=N1 MTPVBMVUENFFLL-HXUWFJFHSA-N 0.000 claims description 4
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 4
- 229960000402 palivizumab Drugs 0.000 claims description 4
- 229960000329 ribavirin Drugs 0.000 claims description 4
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 4
- KSHJXDWYTZJUEI-UHFFFAOYSA-N 1-cyclopropyl-3-[[1-(4-hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one Chemical compound N=1C2=CC=CC=C2N(CCCCO)C=1CN(C1=O)C2=CN=CC=C2N1C1CC1 KSHJXDWYTZJUEI-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 108700002314 gontivimab Proteins 0.000 claims description 3
- 229960001521 motavizumab Drugs 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- BLUJRJMLDHEMRX-UHFFFAOYSA-N 2-[[2-hydroxy-5-[(5-methyltetrazol-1-yl)iminomethyl]phenyl]-(4-hydroxyphenyl)methyl]-4-[(5-methyltetrazol-1-yl)iminomethyl]phenol Chemical compound Cc1nnnn1N=Cc1ccc(O)c(c1)C(c1ccc(O)cc1)c1cc(C=Nn2nnnc2C)ccc1O BLUJRJMLDHEMRX-UHFFFAOYSA-N 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000013160 medical therapy Methods 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 7
- 239000000543 intermediate Substances 0.000 description 358
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 245
- 239000000243 solution Substances 0.000 description 136
- 238000002360 preparation method Methods 0.000 description 127
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 124
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 117
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 103
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 97
- 230000002829 reductive effect Effects 0.000 description 95
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 94
- 239000011541 reaction mixture Substances 0.000 description 92
- 235000019439 ethyl acetate Nutrition 0.000 description 90
- 229910001868 water Inorganic materials 0.000 description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 71
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 65
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 65
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
- 238000006243 chemical reaction Methods 0.000 description 53
- 238000005160 1H NMR spectroscopy Methods 0.000 description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 52
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 52
- 238000004128 high performance liquid chromatography Methods 0.000 description 50
- 239000007787 solid Substances 0.000 description 50
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 45
- 239000004480 active ingredient Substances 0.000 description 45
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 44
- 238000009472 formulation Methods 0.000 description 42
- 239000012267 brine Substances 0.000 description 37
- MPVDXIMFBOLMNW-UHFFFAOYSA-N chembl1615565 Chemical compound OC1=CC=C2C=C(S(O)(=O)=O)C=C(S(O)(=O)=O)C2=C1N=NC1=CC=CC=C1 MPVDXIMFBOLMNW-UHFFFAOYSA-N 0.000 description 37
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 37
- 239000000047 product Substances 0.000 description 34
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 33
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 32
- 125000006239 protecting group Chemical group 0.000 description 31
- 239000002904 solvent Substances 0.000 description 29
- 238000010898 silica gel chromatography Methods 0.000 description 28
- 239000012044 organic layer Substances 0.000 description 27
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 26
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 25
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 25
- 239000000843 powder Substances 0.000 description 25
- 125000000217 alkyl group Chemical group 0.000 description 24
- 239000002585 base Substances 0.000 description 24
- 150000002148 esters Chemical class 0.000 description 24
- 208000015181 infectious disease Diseases 0.000 description 24
- 125000001424 substituent group Chemical group 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 22
- 238000000746 purification Methods 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- 239000003921 oil Substances 0.000 description 20
- 239000003960 organic solvent Substances 0.000 description 20
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 20
- 239000002253 acid Substances 0.000 description 19
- 150000001412 amines Chemical class 0.000 description 19
- 239000000463 material Substances 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- 239000000377 silicon dioxide Substances 0.000 description 19
- 241000282414 Homo sapiens Species 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 239000002245 particle Substances 0.000 description 18
- 239000000546 pharmaceutical excipient Substances 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- 239000000725 suspension Substances 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 229910052681 coesite Inorganic materials 0.000 description 17
- 229910052906 cristobalite Inorganic materials 0.000 description 17
- 229940079593 drug Drugs 0.000 description 17
- 239000000651 prodrug Substances 0.000 description 17
- 229940002612 prodrug Drugs 0.000 description 17
- 229910052682 stishovite Inorganic materials 0.000 description 17
- 229910052905 tridymite Inorganic materials 0.000 description 17
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000001816 cooling Methods 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- 239000007858 starting material Substances 0.000 description 16
- 239000003039 volatile agent Substances 0.000 description 16
- 150000001299 aldehydes Chemical class 0.000 description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- 239000011780 sodium chloride Substances 0.000 description 15
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 14
- 239000007821 HATU Substances 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 239000000443 aerosol Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 13
- 235000011054 acetic acid Nutrition 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 241000124008 Mammalia Species 0.000 description 11
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
- 150000001345 alkine derivatives Chemical class 0.000 description 10
- 125000005842 heteroatom Chemical group 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 230000000670 limiting effect Effects 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 238000002953 preparative HPLC Methods 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- 229910019213 POCl3 Inorganic materials 0.000 description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 9
- 239000003607 modifier Substances 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- 238000002390 rotary evaporation Methods 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- 239000011593 sulfur Substances 0.000 description 9
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 125000003710 aryl alkyl group Chemical group 0.000 description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 125000006413 ring segment Chemical group 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 241000711920 Human orthopneumovirus Species 0.000 description 7
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 7
- 239000004698 Polyethylene Substances 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 239000000839 emulsion Substances 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 7
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000006071 cream Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000003995 emulsifying agent Substances 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
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- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 239000006199 nebulizer Substances 0.000 description 6
- 238000012856 packing Methods 0.000 description 6
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
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- 238000002560 therapeutic procedure Methods 0.000 description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 5
- MSJXONVQCMKJDI-UHFFFAOYSA-N 5-chloro-2-(methanesulfonamido)benzoic acid Chemical compound CS(=O)(=O)NC1=CC=C(Cl)C=C1C(O)=O MSJXONVQCMKJDI-UHFFFAOYSA-N 0.000 description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Substances ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 5
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 5
- 206010062106 Respiratory tract infection viral Diseases 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 125000002947 alkylene group Chemical group 0.000 description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 239000007900 aqueous suspension Substances 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 238000002648 combination therapy Methods 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000002270 dispersing agent Substances 0.000 description 5
- 229940112141 dry powder inhaler Drugs 0.000 description 5
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 5
- 239000003925 fat Substances 0.000 description 5
- 235000019197 fats Nutrition 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 235000013355 food flavoring agent Nutrition 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 5
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 5
- 239000002207 metabolite Substances 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
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- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- OVCXRBARSPBVMC-UHFFFAOYSA-N triazolopyridine Chemical compound C=1N2C(C(C)C)=NN=C2C=CC=1C=1OC=NC=1C1=CC=C(F)C=C1 OVCXRBARSPBVMC-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229950008396 ulobetasol propionate Drugs 0.000 description 1
- BDSYKGHYMJNPAB-LICBFIPMSA-N ulobetasol propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]2(C)C[C@@H]1O BDSYKGHYMJNPAB-LICBFIPMSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Definitions
- Pneumovirinae viruses are negative-sense, single-stranded, RNA viruses that are responsible for many prevalent human and animal diseases.
- the Pneumovirinae sub-family of viruses is a part of the family Paramyxoviridae and includes human respiratory syncytial virus (HRSV). Almost all children will have had an HRSV infection by their second birthday. HRSV is the major cause of lower respiratory tract infections in infancy and childhood with 0.5% to 2% of those infected requiring hospitalization.
- the elderly and adults with chronic heart, lung disease or those that are immunosuppressed also have a high risk for developing severe HRSV disease (www.cdc.gov/rsv/index.html). No vaccine to prevent HRSV infection is currently available.
- the monoclonal antibody palivizumab is available for immunoprophylaxis, but its use is restricted to infants at high risk, e.g., premature infants or those with either congenital heart or lung disease, and the cost for general use is often prohibitive.
- the nucleoside analog ribavirin has been approved as the only antiviral agent to treat HRSV infections but has limited efficacy. Therefore, there is a need for anti- Pneumovirinae therapeutics.
- Douglas et al., Antimicrobial agents and chemotherapy, vol. 49, no. 6, 2005 discloses small molecules VP-14637 and JNJ-2408068 as inhibitors of respiratory syncticial virus fusion.
- WO 2012/012776 A1 discloses methods for treating Paramyxoviridae virus infections by administering certain ribosides, riboside phosphates and prodrugs thereof.
- WO 2011/149856 A1 discloses compounds, pharmaceutical compositions and combination therapies for inhibition of hepatitis C.
- US 2010/215616 A1 discloses compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection.
- WO 2011/015658 A1 discloses certain bis-benzimidazole derivatives as hepatitis C virus inhibitors.
- one embodiment provides a compound of formula I: or a pharmaceutically acceptable salt thereof; wherein:
- One embodiment provides a compound of formulas 1-103 (i.e., compounds 1-103 as described in examples 117- 218), or a salt thereof.
- One embodiment provides a compound of formula I (including compounds 104-122 of examples 219-237) or a stereoisomer (e.g., enantiomer, diasteromer, atropisomer) or a salt thereof or a compound of formulas 1-103 or a stereoisomer (e.g., enantiomer, diasteromer, atropisomer) or a salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier.
- One embodiment provides a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof) for use in a method of treating a Pneumovirinae infection in a mammal (e.g., a human) in need thereof.
- a pharmaceutically acceptable salt thereof e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof
- One embodiment provides a tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate of a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof) for use in a method of treating a Pneumovirinae infection in a mammal (e.g., a human) in need thereof.
- a pharmaceutically acceptable salt thereof e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof
- One embodiment provides a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof) for use in a method of treating a respiratory syncytial virus infection in a mammal (e.g., a human) in need thereof.
- a pharmaceutically acceptable salt thereof e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof
- One embodiment provides a tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate of a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof) for use in a method of treating a respiratory syncytial virus infection in a mammal (e.g., a human) in need thereof.
- a pharmaceutically acceptable salt thereof e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof
- One embodiment provides a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable diluent or carrier for use in a method of treating a Pneumovirinae infection (e.g., a respiratory syncytial virus infection) in a mammal (e.g., a human) in need thereof.
- a Pneumovirinae infection e.g., a respiratory syncytial virus infection
- One embodiment provides a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof), in combination with at least one additional therapeutic agent for use in a method of treating a Pneumovirinae infection (e.g., a respiratory syncytial virus infection) in a mammal (e.g., a human) in need thereof.
- a Pneumovirinae infection e.g., a respiratory syncytial virus infection
- mammal e.g., a human
- One embodiment provides a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof) for use in medical therapy.
- a pharmaceutically acceptable salt thereof e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof
- One embodiment provides a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof for use in the prophylactic or therapeutic treat a viral infection caused by a Pneumovirinae virus or a respiratory syncytial virus.
- a pharmaceutically acceptable salt thereof e.g., a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof for use in the prophylactic or therapeutic treat a viral infection caused by a Pneumovirinae virus or a respiratory syncytial virus.
- alkyl refers to a straight or branched hydrocarbon.
- an alkyl group can have 1 to 20 carbon atoms ( i.e, C 1 -C 20 alkyl), 1 to 8 carbon atoms ( i.e., C 1 -C 8 alkyl), or 1 to 6 carbon atoms ( i.e., C 1 -C 6 alkyl).
- alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )
- alkoxy refers to a group having the formula -O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom.
- the alkyl portion of an alkoxy group can have 1 to 20 carbon atoms ( i.e., C 1 -C 20 alkoxy), 1 to 12 carbon atoms ( i.e., C 1 -C 12 alkoxy), or 1 to 6 carbon atoms ( i.e., C 1 -C 6 alkoxy).
- alkoxy groups include, but are not limited to, methoxy (-O-CH 3 or -OMe), ethoxy (-OCH 2 CH 3 or -OEt), t-butoxy (-O-C(CH 3 ) 3 or -OtBu).
- haloalkyl refers to an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom.
- the alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms ( i.e., C 1 -C 20 haloalkyl), 1 to 12 carbon atoms ( i.e ., C 1 -C 12 haloalkyl), or 1 to 6 carbon atoms ( i.e ., C 1 -C 6 alkyl).
- suitable haloalkyl groups include, but are not limited to, -CF 3 , -CHF 2 , -CFH 2 , -CH 2 CF 3 .
- alkenyl refers to a straight or branched hydrocarbon with at least one site of unsaturation, i.e., a carbon-carbon, sp 2 double bond.
- an alkenyl group can have 2 to 20 carbon atoms ( i.e., C 2 -C 20 alkenyl), 2 to 8 carbon atoms ( i.e., C 2 -C 8 alkenyl), or 2 to 6 carbon atoms ( i.e., C 2 -C 6 alkenyl).
- alkynyl refers to a straight or branched hydrocarbon with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond.
- an alkynyl group can have 2 to 20 carbon atoms ( i.e., C 2 -C 20 alkynyl), 2 to 8 carbon atoms ( i.e., C 2 -C 8 alkyne,), or 2 to 6 carbon atoms ( i.e., C 2 -C 6 alkynyl).
- halogen or halo refers to F, Cl, Br, or I.
- aryl refers to an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
- an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms.
- Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl.
- arylalkyl refers to an acyclic alkyl radical as described herein in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl radical as described herein.
- Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
- the arylalkyl group can comprise 7 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
- substituted in reference to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc.
- substituted alkyl for example, "substituted alkyl”, “substituted alkylene”, “substituted aryl”, “substituted arylalkyl”, “substituted heterocyclyl”, and “substituted carbocyclyl”, unless otherwise indicated, means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl, respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent.
- Alkylene, alkenylene, and alkynylene groups may also be similarly substituted. Unless otherwise indicated, when the term "substituted" is used in conjunction with groups such as arylalkyl, which have two or more moieties capable of substitution, the substituents can be attached to the aryl moiety, the alkyl moiety, or both.
- heterocycle or “heterocyclyl” as used herein includes by way of example and not limitation those heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968 ), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28 ; and J. Am. Chem. Soc. (1960) 82:5566 .
- heterocycle includes a “carbocycle” as defined herein, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g., O, N, or S).
- heterocycle or “heterocyclyl” includes saturated rings, partially unsaturated rings, and aromatic rings ( i.e., heteroaromatic rings).
- Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl groups.
- a non-limiting example of a carbonyl substituted heterocyclyl is:
- heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl
- carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
- carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
- nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
- nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
- heterocyclyl refers to a monocyclic heterocyclyl ring or a polycyclic heterocyclyl ring, wherein the monocyclic heterocyclyl ring or polycyclic heterocyclyl ring has between 2-20 carbon atoms in the ring system and 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring system, which heterocyclyl is also referred to as a C 2 -C 20 heterocyclyl.
- the C 2 -C 20 heterocyclyl can be saturated, partially unsaturated or aromatic.
- the rings of a polycyclic C 2 -C 20 heterocyclyl can be connected to one another by fused, bridged or spiro bonds.
- heteroaryl refers to an aromatic heterocyclyl having at least one heteroatom in the ring.
- suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, and nitrogen.
- suitable heteroatoms include oxygen, sulfur, and nitrogen.
- suitable heteroaryl rings include all of those aromatic rings listed in the definition of "heterocyclyl", including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.
- heterocyclylalkyl refers to an acyclic alkyl radical as described herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heterocyclyl radical as described herein. It is to be understood that the hetereocyclyl can be connected to the alkyl group at any acceptable carbon or heteroatom of the hetereocyclyl.
- Typical, but non-limiting, examples of heterocyclylalkyl groups include pyridylmethyl, pyrimidinylethyl, piperidinylmethyl and 1-imidazolylethyl.
- Carbocycle refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
- Monocyclic carbocycles have 3 to 7 ring atoms, still more typically 5 or 6 ring atoms.
- Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system, or spirofused rings.
- Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and phenyl.
- Non-limiting examples of bicyclo carbocycles includes naphthyl, tetrahydronapthalene, and decaline.
- cycloalkyl refers to a saturated or partially unsaturated ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
- Monocyclic cycloalkyl groups have 3 to 7 ring atoms, still more typically 5 or 6 ring atoms.
- Bicyclic cycloalkyl groups have 7 to 12 ring atoms, e.g., arranged as a bicyclo (4,5), (5,5), (5,6) or (6,6) system, or 9 or 10 ring atoms arranged as a bicyclo (5,6) or (6,6) system.
- Cycloalkyl groups include hydrocarbon mono-, bi-, and poly-cyclic rings, whether fused, bridged, or spiro.
- monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclehex-2-enyl, 1-cyclohex-3-enyl, bicyclo[3.1.0] hex-6-yl.
- cycloalkylalkyl refers to an acyclic alkyl radical as described herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with a cycloalkyl radical as described herein.
- Typical, but non-limiting, examples of carbocyclylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
- carbocyclylalkyl refers to an acyclic alkyl radical as described herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with a carbocyclyl radical as described herein.
- Typical, but non-limiting, examples of carbocyclylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
- optionally substituted in reference to a particular moiety of the compound of formula I (e.g., an optionally substituted aryl or alkyl group) refers to a moiety wherein all substitutents are hydrogen or wherein one or more of the hydrogens of the moiety may be replaced by substituents such as those listed under the definition of "substituted” or as otherwise indicated.
- Selected substituents comprising the compounds of formula I may be present to a recursive degree.
- "recursive substituent” means that a substituent may recite another instance of itself. The multiple recitations may be direct or indirect through a sequence of other substituents. Because of the recursive nature of such substituents, theoretically, a large number of compounds may be present in any given embodiment.
- One of ordinary skill in the art of medicinal chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by way of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.
- Recursive substituents may be an intended aspect of the invention.
- One of ordinary skill in the art of medicinal chemistry understands the versatility of such substituents.
- Protecting group refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole.
- the chemical substructure of a protecting group varies widely.
- One function of a protecting group is to serve as an intermediate in the synthesis of the parental drug substance.
- Chemical protecting groups and strategies for protection/deprotection are well known in the art. See: “ Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991 .
- Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g. making and breaking chemical bonds in an ordered and planned fashion.
- Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools.
- Chemically protected intermediates may themselves be biologically active or inactive.
- Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs.
- Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug.
- Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
- prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e., active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s).
- a prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.
- Prodrug moiety means a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process ( Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191 ).
- Enzymes which are capable of an enzymatic activation mechanism with, for example any phosphate or phosphonate prodrug compounds of the invention include but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases.
- Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy.
- a prodrug moiety may include an active metabolite or drug itself.
- a compound of formula I or a compound of formulas 1-103, and their pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs.
- crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures. The crystalline polymorphism may result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism).
- crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in different crystal structures.
- the pseudopolymorphs of the instant invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformers of the same molecule (conformational pseudopolymorphism).
- the instant invention comprises all polymorphs and pseudopolymorphs of the compounds of formula I and formulas 1-103, and their pharmaceutically acceptable salts.
- a compound of formula I or a compound of formulas 1-103 and their pharmaceutically acceptable salts may also exist as an amorphous solid.
- an amorphous solid is a solid in which there is no long-range order of the positions of the atoms in the solid. This definition applies as well when the crystal size is two nanometers or less.
- Additives, including solvents, may be used to create the amorphous forms of the instant invention.
- the instant invention comprises all amorphous forms of the compounds of formula I and formulas 1-103 and their pharmaceutically acceptable salts.
- treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
- treatment refers to the act of treating, as “treating” is defined immediately above.
- terapéuticaally effective amount is the amount of compound of formula I or a compound of formulas 1-103 present in a composition described herein that is needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a composition is administered by the chosen route of administration.
- the precise amount will depend upon numerous factors, for example the particular compound of formula I or the compound of formulas 1-103, the specific activity of the composition, the delivery device employed, the physical characteristics of the composition, its intended use, as well as patient considerations such as severity of the disease state, patient cooperation, etc., and can readily be determined by one skilled in the art and in reference to the information provided herein.
- normal saline means a water solution containing 0.9% (w/v) NaCl.
- hypertonic saline means a water solution containing greater than 0.9% (w/v) NaCl.
- 3% hypertonic saline would contain 3% (w/v) NaCl.
- any reference to the compounds of the invention described herein also includes a reference to a physiologically acceptable salt (e.g., pharmaceutically acceptable salt) thereof.
- physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal or an alkaline earth (for example, Na + , Li + , K + , Ca +2 and Mg +2 ), ammonium and NR 4 + (wherein R is defined herein).
- Physiologically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid
- Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NR 4 + .
- each R is independently H or (C 1 -C 6 )alkyl.
- salts of active ingredients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
- salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present disclosure.
- compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
- racemic mixture A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
- racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
- the compounds disclosed herein, exemplified by formula I and formulas 1-103 may have chiral centers, e.g. chiral carbon.
- the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers.
- Individual enantiomers or diasteromers, isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention.
- stereoisomeric mixtures are separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances.
- optically active adjuncts e.g., acids or bases followed by conversion back to the optically active substances.
- the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
- chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
- stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
- Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography. Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
- the compounds of the invention are greater than 50% a single enantiomer. In another embodiment, the compounds of the invention are at least 51% a single enantiomer. In another embodiment, the compounds of the invention are at least 60% a single enantiomer. In another embodiment, the compounds of the invention are at least 70% a single enantiomer. In another embodiment, the compounds of the invention are at least 80% a single enantiomer. In another embodiment, the compounds of the invention are at least 90% a single enantiomer. In another embodiment, the compounds of the invention are at least 95% a single enantiomer. In another embodiment, the compounds of the invention are at least 98% a single enantiomer.
- the compounds of the invention are at least 99% a single enantiomer. In another embodiment, the compounds of the invention are greater than 50% a single diasteromer. In another embodiment, the compounds of the invention are at least 51% a single diasteromer. In another embodiment, the compounds of the invention are at least 60% a single diastereomer. In another embodiment, the compounds of the invention are at least 70% a single diastereomer. In another embodiment, the compounds of the invention are at least 80% a single diastereomer. In another embodiment, the compounds of the invention are at least 90% a single diastereomer. In another embodiment, the compounds of the invention are at least 95% a single diastereomer. In another embodiment, the compounds of the invention of are at least 98% a single diastereomer. In another embodiment, the compounds of the invention are at least 99% a single diastereomer.
- the chirality at the asterisk position is a feature of these certain compounds of formula Ic (as well as compounds of related formulas).
- the stereochemistry at the carbon marked with an asterisk as shown above for formula Ic is the (S) stereochemistry provided that A is ranked the lowest (3) or highest (1) of the three substituents of the asterisk carbon following the Cahn-Ingold-Prelog system or the (R) stereochemistry provided that A is ranked number 2 of the three substituents of the asterisk carbon following the Cahn-Ingold-Prelog system ( March, J., Advanced Organic Chemistery, 4th Addition, John Wiley and Sons, pages 109-111 ).
- the compounds of the invention of formula Ic are greater than 50% a single stereoisomer at the asterisk position.
- the compounds of the invention of formula Ic are at least 60% a single stereoisomer at the asterisk position.
- the compounds of the invention of formula Ic are at least 70% a single stereoisomer at the asterisk position.
- the compounds of the invention of formula Ic are at least 80% a single stereoisomer at the asterisk position.
- the compounds of the invention of formula Ic are at least 90% a single stereoisomer at the asterisk position.
- the compounds of the invention of formula Ic are at least 95% a single stereoisomer at the asterisk position.
- Certain compounds disclosed herein including compounds of the invention can be represented by formula II (and salts thereof) as shown below wherein a position of chirality is marked with an asterisk.
- This formula is representative of compounds 1-103 wherein the R, X and Ar groups in formula II represent the corresponding groups of the compounds 1-103.
- the chirality at the asterisk position is a feature of these certain compounds of the invention of formula II (as well as compounds of related formulas).
- the stereochemistry at the carbon marked with an asterisk as shown above for formula II is the (S) stereochemistry.
- the compounds of the invention represented by formula II are greater than 50% a single stereoisomer at the asterisk position.
- the compounds of the invention represented by formula II are at least 60% a single stereoisomer at the asterisk position.
- the compounds of the invention represented by formula II are at least 70% a single stereoisomer at the asterisk position.
- the compounds of the invention represented by formula II are at least 80% a single stereoisomer at the asterisk position.
- the compounds of the invention represented by formula II are at least 90% a single stereoisomer at the asterisk position.
- the compounds of the invention represented by formula II are at least 95% a single stereoisomer at the asterisk position.
- Compounds disclosed herein including compounds of formula I and formulas 1-103 also include molecules that incorporate isotopes of the atoms specified in the particular molecules.
- Non-limiting examples of these isotopes include D, T, 14 C, 13 C and 15 N.
- the compounds of the invention can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.
- a specific group of compounds of formula I are compounds of formula Ia: and salts thereof.
- Another specific group of compounds of formula I are compounds of formula Ig: and salts thereof.
- Another specific group of compounds of formula I are compounds of formula Im: and salts thereof.
- Another specific group of compounds of formula I are compounds of formula In: and salts thereof.
- Additional specific groups of compounds of formula I are compounds of formula Ip1, Ip2, Ip3 or Ip4: or a salt thereof.
- Additional specific groups of compounds of formula I are compounds of formula Iq1, Iq2, Iq3 or Iq4: or a salt thereof.
- Additional specific groups of compounds of formula I are compounds of formula Ir1, Ir2, Ir3 or Ir4: or a salt thereof.
- Additional specific groups of compounds of formula I are compounds of formula Iu1, Iu2, Iu3 or Iu4: or a salt thereof.
- Additional specific groups of compounds of formula I are compounds of formula Iw1, Iw2, Iw3 or Iw4: or a salt thereof.
- a specific group of compounds of formula I are compounds wherein each R 3 and each R 3' is H.
- a specific value for R 3 is H.
- a specific value for R 3' is H.
- n 3
- a specific group of compounds of formula I are compounds wherein each p is 2.
- a specific group of compounds of formula I are compounds wherein each R 4 and each R 4' is H.
- a specific value for R 4 is H.
- a specific value for R 4' is H.
- a specific value for A is -(CH 2 ) 3 -.
- Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each selected so that the ring formed by Y 1 , Y 2 , Y 4 , Y 5 and the carbon atom connected to Y 1 and Y 5 is an aromatic ring.
- Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each selected so that the ring formed by Y 1 , Y 2 , Y 4 , Y 5 and the carbon atom connected to Y 1 and Y 5 is an aromatic ring
- the dashed bonds (----) are selected from single bonds and double bonds so that the ring formed by Y 1 , Y 2 , Y 4 , Y 5 along with the carbon atom connected to Y 1 and Y 5 is an aromatic ring.
- a specific value for Y 1 is N.
- a specific value for Y 5 is CR 2 .
- a specific value for R 2 is H.
- a specific value for R 2' is H.
- a specific value for R 8' is H.
- a specific group of compounds of formula I are compounds wherein R 2' , R 2 and R 8' are each H.
- R 7 is H or (C 1 -C 8 )alkyl.
- R 7 is H or (C 1 -C 2 )alkyl.
- R 7 Another specific value for R 7 is H or methyl.
- R 1 is H, -NR 11 R 12 , (C 1 -C 8 )alkyl or C 2 -C 20 heterocyclyl.
- R 1 is H, (C 1 -C 8 )alkyl or C 2 -C 20 heterocyclyl.
- R 1 is H, -NR 11 R 12 or (C 1 -C 8 )alkyl.
- R 1 is H, (C 1 -C 3 )alkyl or -NR 11 R 12 , wherein each R 11 or R 12 is independently H or (C 1 -C 3 )alkyl; or R 11 and R 12 together with the nitrogen to which they are both attached to form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, -S-, -S(O) p -, -NH-, -NR a - or -C(O)-.
- R 1 is H, (C 1 -C 3 )alkyl or -NR 11 R 12 , wherein each R 11 or R 12 is independently H or (C 1 -C 3 )alkyl; or R 11 and R 12 together with the nitrogen to which they are both attached to form a 4 to 5 membered heterocyclic ring.
- R 1 Another specific value for R 1 is H, methyl or azetidinyl.
- R 1 is H, (C 1 -C 8 )alkyl or C 2 -C 20 heterocyclyl.
- R 1 is H, (C 1 -C 8 )alkyl or 3-7 membered monocyclic saturated heterocyclyl.
- R 1 is H, (C 1 -C 8 )alkyl or 3-7 membered monocyclic saturated heterocyclyl wherein the 3-7 membered monocyclic saturated heterocyclyl includes 2-6 carbon atoms in the ring and 1-3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring.
- R 1 is H, (C 1 -C 3 )alkyl or 3-7 membered monocyclic saturated heterocyclyl wherein the 3-7 membered monocyclic saturated heterocyclyl includes 2-6 carbon atoms in the ring and 1-3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring.
- R 1 is H, (C 1 -C 3 )alkyl or 4-5 membered monocyclic saturated heterocyclyl wherein the 4-5 membered monocyclic saturated heterocyclyl includes 3-4 carbon atoms in the ring and 1hetereoatom selected from oxygen, sulfur and nitrogen in the ring.
- R 8 is (C 1 -C 8 )alkyl or 3-7 membered monocyclic saturated heterocyclyl, wherein the 3-7 membered monocyclic saturated heterocyclyl is optionally substituted with one or more hydroxy, NH 2 or CN.
- R 8 is (C 1 -C 8 )alkyl or 3-7 membered monocyclic saturated heterocyclyl, wherein the 3-7 membered monocyclic saturated heterocyclyl includes 2-6 carbon atoms in the ring and 1-3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, and wherein the 3-7 membered monocyclic saturated heterocyclyl is optionally substituted with one or more hydroxy, NH 2 or CN.
- R 8 is (C 1 -C 3 )alkyl or 3-7 membered monocyclic saturated heterocyclyl wherein 3-7 membered monocyclic saturated heterocyclyl is optionally substituted with one or more hydroxy, NH 2 or CN.
- R 8 is (C 1 -C 3 )alkyl or 3-7 membered monocyclic saturated heterocyclyl, wherein the 3-7 membered monocyclic saturated heterocyclyl includes 2-6 carbon atoms in the ring and 1-3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, and wherein 3-7 membered monocyclic saturated heterocyclyl is optionally substituted with one or more hydroxy, NH 2 or CN.
- R 8 is (C 1 -C 2 )alkyl or 4-5 membered monocyclic saturated heterocyclyl, wherein the 4-5 membered monocyclic saturated heterocyclyl includes 3-4 carbon atoms in the ring and one nitrogen atom in the ring, and wherein the 4-5 membered monocyclic saturated heterocyclyl is optionally substituted with one or more hydroxy, NH 2 or CN.
- R 8 is methyl, azetidinyl or pyrrolidinyl, wherein azetidinyl or pyrrolidinyl is optionally substituted with one or more hydroxy, NH 2 or CN.
- a specific group of compounds of formula I are compounds wherein each R a is (C 1 -C 8 )alkyl.
- a specific group of compounds of formula I are compounds wherein each R a is (C 1 -C 3 )alkyl.
- a specific group of compounds of formula I are compounds wherein each R a is (C 1 -C 2 )alkyl.
- a specific group of compounds of formula I are compounds wherein each R a is methyl.
- a specific group of compounds of formula I are compounds wherein X is -C(R 13 )(R 14 )- or X is absent.
- a specific value for R 13 is H.
- R 14 is -NR 11 S(O) p R a .
- R 14 is -NHS(O) 2 (C 1 -C 3 )alkyl.
- R 14 is -NHS(O) 2 CH 3 .
- a specific group of compounds of formula I are compounds R 13 is H and R 14 is -NR 11 S(O) p R a .
- a specific group of compounds of formula I are compounds R 13 is H and R 14 is -NHS(O) 2 (C 1 -C 3 )alkyl.
- a specific group of compounds of formula I are compounds wherein R 13 is H and R 14 is -NHS(O) 2 CH 3 .
- a specific group of compounds of formula I are compounds wherein X is -C(H)(NHS(O) 2 CH 3 )- or X is absent.
- a specific group of compounds of formula I are compounds wherein X is absent.
- a specific value for Ar is a phenyl or a pyridyl wherein the phenyl or pyridyl is optionally substituted with 1 to 5 R 6 .
- Ar is a phenyl or 5-6 membered monocyclic heteroaryl, wherein phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1 to 5 R 6 .
- Ar is a phenyl, pyridinyl or thienyl, wherein phenyl, pyridinyl or thienyl is optionally substituted with 1 to 5 R 6 .
- R 6 is -NR 11 S(O) p R a , halogen, (C 1 -C 8 )alkyl or NR 11 C(O)R 11 .
- R 6 is -NR 11 S(O) p R a , halogen or (C 1 -C 8 )alkyl.
- R 6 Another specific value for R 6 is -NHS(O) 2 (C 1 -C 3 )alkyl, halogen or (C 1 -C 3 )alkyl.
- R 6 Another specific value for R 6 is -NHS(O) 2 CH 3 , chloro, bromo or methyl.
- the compounds of formula I do not include compounds wherein Y 3 is N and R 1 is OH.
- the compounds of formula I are selected from compounds compound of formula I, or a salt thereof; wherein:
- a compound of formula I is selected from: 23. and and salts thereof.
- a compound of the invention is selected from: and and salts thereof.
- esters of compounds of the invention are esters of compounds of the invention.
- esters of the compounds of the invention. Accordingly, one example of esters of the compounds of the invention include esters wherein a hydroxyl group of the compound of the invention is an ester. These esters of compounds of the invention are typically labile and thus the ester may be converted to the corresponding hydroxyl group in vivo (e.g., after administration). Esters include those esters based on carbon and phosphorus.
- General Scheme 1 describes the methods under which the compounds of the invention A7 can be prepared.
- the starting material is a protected (PG) cycloaminoalkyl ring that can be 6-, 7- or larger size ring and also optionally contain substituents around the ring.
- This cycloaminoalkyl ring is substituted at the carbon atom adjacent to the nitrogen group with a methyl ester group.
- the stereochemistry at this position is the (S) stereochemistry.
- Protecting groups on the cycloaminoalkyl nitrogen can be removed during the synthesis using methods described in Green and Wutts, Protecting Groups in Organic Synthesis 3rd Editi on.
- the carboxylic acid methyl ester group on N-protected cycloaminoalkyl A1 is first converted to the enol ether utilizing a solution of Tebbe Reagent to yield A2.
- Tebbe Reagent e.g., Tebbe Reagent
- the ester is reacted with the Tebbe reagent at low temperature (-78 °C) and in a suitable solvent (e.g., dry THF).
- the product A2 is then transformed into alpha-bromo ketone A3 via bromination of enol ether. This transformation is carried out using bromination reagents such as NBS in a mixed solvent (e.g. THF and water).
- Formation of imidazopyridine A5 is then achieved via condensation of A3 with a 2-aminopyridine e.g. A4 in the presence of a base e.g. sodium bicarbonate under elevated temperatures.
- a base e.g. sodium bicarbonate under elevated temperatures.
- Removal of the protecting group on the cycloalkylamine e.g. BOC or CBZ is done using procedures described in Green and Wutts, Protecting Groups in Organic Synthesis 3rd Edition to provide A6 .
- BOC groups are removed using TFA in an organic solvent (e.g. dichloromethane), or treatment with phosphoric acid.
- the unprotected NH in the cycloaminoalkyl ring on A6 is acylated to provide compounds of structure A7 using standard acylation procedures.
- an acid chloride generated from the corresponding acid using thionyl chloride or oxalyl chloride, is reacted with A6 in the presence of an organic base, e.g. triethylamine, in an organic solvent e.g. dichloromethane.
- an organic base e.g. triethylamine
- an organic solvent e.g. dichloromethane.
- a peptide coupling of A6 with an acid can be performed using a variety of standard coupling agents.
- A6 is acylated by first, combining HATU and the acid together in an organic solvent e.g. DMF, and then after a short period of time e.g. 30 min adding the amine A6 and an organic base e.g. triethylamine to generate A7
- the starting material A3 (general scheme 1) is a protected (PG) cycloaminoalkyl ring that can be 6-, 7- or larger size ring and also optionally contain substituents around the ring. This cycloaminoalkyl ring is substituted at the carbon atom adjacent to the nitrogen group with a halo ketone. In one embodiment the stereochemistry at this position is the (S) stereochemistry.
- Protecting groups on the cycloaminoalkyl nitrogen can be removed during the synthesis using methods described in Green and Wutts, Protecting Groups in Organic Synthesis 3rd Editi on.
- Removal of the protecting group on the cycloalkylamine e.g. BOC or CBZ is done using procedures described in Green and Wutts, Protecting Groups in Organic Synthesis 3rd Edition to provide B3 .
- BOC groups are removed using TFA in an organic solvent (e.g. dichloromethane) or treatment with phosphoric acid.
- the unprotected NH in the cycloaminoalkyl ring on B3 is acylated to provide compounds of structure B4 using standard acylation procedures.
- an acid chloride generated from the corresponding acid using thionyl chloride or oxalyl chloride, is reacted with B3 in the presence of an organic base, e.g. triethylamine, in an organic solvent e.g. dichloromethane.
- an organic base e.g. triethylamine
- an organic solvent e.g. dichloromethane.
- a peptide coupling of B3 with an acid can be performed using a variety of standard coupling agents.
- B3 is acylated by first, combining HATU and the acid together in an organic solvent e.g. DMF, and then after a short period of time e.g. 30 min adding the amine B3 and an organic base e.g. triethylamine to generate B4.
- B5 Displacement of the chloride in B4 with nucleophilic amines is then performed to form B5.
- a base e.g. triethylamine and the appropriate amine at elevated temperatures above 50 °C forms B5.
- any protecting groups remaining on compounds B5 are then removed using conditions as described in Green and Wutts, Protecting Groups in Organic Synthesis 3rd Editi on to yield compounds of type B6.
- General scheme 3 describes the methods under which the compounds of the invention C5 can be prepared.
- the starting material is a protected (PG) cycloaminoalkyl ring A1 that can be 6-, 7- or larger size ring and also optionally contain substituents around the ring.
- This cycloaminoalkyl ring is substituted at the carbon atom adjacent to the nitrogen group with an ester group.
- the stereochemistry at this position is the (S) stereochemistry.
- Protecting groups on the cycloaminoalkyl nitrogen can be removed during the synthesis using methods described in Green and Wutts, Protecting Groups in Organic Synthesis 3rd Editi on.
- the N-protected cyclic aminoheterocycle A1 is first reacted with the anion of the alpha-methyl substituted pyridine to form C1.
- the anion is generated first by treatment of the pyridine reagent in an organic solvent such as THF with base, preferred (but not limited to) are bases such as BuLi, NaHMDS, LDA or KOi-Bu and then adding A1 .
- the intermediate C1 is then converted to C2 by treatment with hydroxylamine.
- a typical produce includes treatment of the ketone in ethanolic solution with hydroxylamine in the presence of sodium acetate to provide C2.
- the pyridine nitrogen in C2 is aminated by using a variety of reagents described in the literature for this transformation, such as hydroxylamine-o-sulphonic acid, O-(diphenyl-phosphinyl)hydroxylamine/ hydrogen iodide, O-(2,4-dinitrophenyl)hydroxylamine and the like.
- C2 is dissolved in a suitable organic solvent (e.g. acetonitrile) and treated with the amination reagent in the presence of base, e.g. cesium carbonate.
- base e.g. cesium carbonate.
- the corresponding aminated pyridine can often be reacted in situ to form the desired cyclised product C3 , or alternatively addition of acid or base can facilitate this transformation to C3.
- the product C3 is then converted to C4 and then C5 as described in Scheme 1 for conversion of A5 to A7 via A6.
- General scheme 4 describes the methods under which the compounds of the invention D6 can be prepared.
- the starting material is a protected (PG) cycloaminoalkyl ring that can be 6-, 7- or larger size ring and also optionally contain substituents around the ring.
- This cycloaminoalkyl ring is substituted at the carbon atom adjacent to the nitrogen group with a methyl ester group.
- the stereochemistry at this position is the (S) stereochemistry.
- Protecting groups on the cycloaminoalkyl nitrogen can be removed during the synthesis using methods described in Green and Wutts, Protecting Groups in Organic Synthesis 3rd Editi on.
- the ester group on the N-protected cyclic aminoheterocycle A1 is first converted to an alkyne D2 via one of the many methods known in the literature, typically via the corresponding aldehyde analog of A1 .
- the aldehyde for example, is formed through reduction of the ester group, using DIBAL in a suitable organic solvent (e.g. dichloromethane, THF, and the like). Conversion of the aldehyde to the alkyne can be achieved by several efficient methods documented in the literature, Corey-Fuchs, Ohira Bestmann reagent and the like. For example, coupling of the aldehyde with triphenylphosphine and carbon tetrabromide in an organic solvent (e.g.
- dichloromethane forms the intermediate dibromoalkene, which is then treated with strong base e.g. nBuLi, in THF at -78C to generate the alkyne.
- base-promoted reactions of dialkyl (diazomethyl) phosphonates (Ohira Bestmann) or (diazomethyl)-trimethylsilane with aldehydes and aryl ketones lead directly to the corresponding homologous alkynes.
- treatment of the aldehyde with the Ohira-Bestmann phosphonate reagent in the presence of potassium carbonate in an alcoholic solvent generates the alkyne.
- the alkyne is then reacted with a bromopyridine under typically, but not limited to, Sonogashira -type conditions and their many variations.
- a bromopyridine under typically, but not limited to, Sonogashira -type conditions and their many variations.
- treatment of the alkyne D2 with the halogenated pyridine in triethylamine in the presence of CuI and a palladium (II) catalyst e.g. PdCl 2 (PPh 3 ) 2 provides D3 .
- the resulting pyridyl alkyne often cyclizes under the reaction conditions to the product D4 or alternatively can be reacted with a fluoride base e.g. TBAF or catalytic amounts of a transition metal to undergo the cyclisation.
- the product D4 is then converted to D5 and then D6 as described in Scheme 1 for conversion of A5 to A7 via A6.
- General scheme 5 describes the methods under which the compounds of the invention E9 can be prepared.
- the starting material is a protected (PG) cycloaminoalkyl ring that can be 6-, 7- or larger size ring and also optionally contain substituents around the ring.
- This cycloaminoalkyl ring is substituted at the carbon atom adjacent to the nitrogen group with an acid group.
- the stereochemistry at this position is the (S) stereochemistry.
- Protecting groups on the cycloaminoalkyl nitrogen can be removed during the synthesis using methods described in Green and Wutts, Protecting Groups in Organic Synthesis 3rd Editi on.
- the carboxylic acid E1 is first activated with a suitable leaving group, for example imidazole.
- the imidazole product E2 is typically generated by treatment of the carboxylic acid with carbonyldiimidazole in an inert organic solvent. Once the acid is activated as the acylimidazole E2, the addition to nitromethane anion is performed. The anion is generated from nitromethane and a strong base (e.g. potassium tert-butoxide), in a solvent such as DMSO, to which E2 is then added to form E3. Reduction of the nitro ketone is then performed to provide E4 using one of a variety of methods described in the literature for reduction of nitro groups.
- a strong base e.g. potassium tert-butoxide
- a solution of the nitro compound in ethanol and acetic acid is reduced with hydrogen gas in the presence of palladium on carbon to generate the amino ketone intermediate E4.
- Reaction of the amino ketone with 1H-pyrazole-1-carboximidamide then generates the amino imidazole intermediate E5.
- This conversion is carried out in the presence of base e.g. sodium carbonate in organic solvent such as ethanol/acetic acid.
- Base e.g. sodium carbonate in organic solvent such as ethanol/acetic acid is used to form bicyclic heterocycle E6 through condensation reactions with unsubstituted and substituted malonates in the presence of a base.
- dimethyl malonate is added to the intermediate E5 in ethanol and treated with sodium ethoxide, followed by heating to provide E6 where Rx is H.
- Scheme 1 describes the methods under which the compounds of the invention F5 can be prepared.
- the starting material is aldehyde F1 described above.
- the aldehyde F1 is first condensed with a hydrazinecarboximidamide and after auto-oxidation generates the amino triazole F2.
- the stereochemistry of the carbon bearing the aldehyde for F1 is the (S) stereochemistry.
- this is performed in an organic solvent e.g. DMF.
- the amino triazole F2 is heated with acetyl acetone in an organic solvent e.g. DMF in the presence of a base e.g. cesium carbonate.
- the product F3 is then converted to F4 and then F5 as described in Scheme 1 for conversion of A5 to A7 via A6.
- General scheme 7 describes the methods under which the compounds of the invention G7 can be prepared.
- the starting material is aldehyde F1 described above and is treated with aminopyridinium intermediates and then cyclised to form the target heterocycles.
- ethyl O-mesityl sulfonyl acetohydroxanate is treated with 70% HClO 4 in dioxane to form the sulfonic acid ammonium salt G2, which is then reacted with an aminopyridine G3 to form the aminopyridinium salt G4.
- G3 is treated with the reagent G2 in an organic solvent such as dichloromethane to form G4. Condensation of G4 with aldehyde F1 affords triazolopyridine G5.
- a typical procedure is to heat the mixture in an organic solvent e.g. DMF in the presence of base e.g. triethylamine.
- the product G5 is then converted to G6 and then G7 as described in Scheme 1 for conversion of A5 to A7 via A6.
- General scheme 8 describes the methods under which the compounds of the invention H4 can be prepared.
- the starting material is bromo ketone A3 described above.
- Compound A3 is reacted with a pyridazine H2 .
- treatment of the bromo ketone A3 in organic solvent e.g. acetonitrile at elevated temperature effects the initial condensation, and then addition of DBU followed by further heating effects the cyclization to afford H1.
- the product H1 is then converted to H3 and then H4 as described in Scheme 1 for conversion of A5 to A7 via A6.
- General scheme 9 describes the methods under which the compounds of the invention 15 can be prepared.
- the starting material is acid E1 described above.
- Acid E1 is first coupled to a diaminopyridine 12 in the presence of an amide coupling reagent followed by subsequent cyclization in the presence of acid to form heterocycle I3.
- compound E1 is reacted with diamino pyridine 12 in an organic solvent e.g. DMF, and in the presence of a coupling reagent, e.g. HATU and base, e.g. triethylamine.
- the mixture is then treated with acid e.g. HOAc and heated at elevated temperature 170°C to form 13.
- the product 13 is then converted to I4 and then I5 as described in Scheme 1 for conversion of A5 to A7 via A6.
- the compounds disclosed herein are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice.
- Tablets will contain excipients, glidants, fillers, binders and the like.
- Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the " Handbook of Pharmaceutical Excipients" (1986 ). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
- the pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
- the formulations both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers and optionally other therapeutic ingredients, particularly those additional therapeutic ingredients as discussed herein.
- the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
- the formulations include those suitable for the foregoing administration routes.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA ). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
- the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be administered as a bolus, electuary or paste.
- a tablet is made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
- the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
- the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
- the active ingredients may be formulated in a cream with an oil-in-water cream base.
- the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
- the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
- the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
- the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
- the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
- Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
- the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
- the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
- Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
- compositions according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
- Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration.
- tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
- Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
- Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
- excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
- Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
- an inert solid diluent for example calcium phosphate or kaolin
- an oil medium such as peanut oil, liquid paraffin or olive oil.
- Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally-occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
- the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
- Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
- Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
- These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
- Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
- a dispersing or wetting agent e.g., sodium tartrate
- suspending agent e.g., sodium EDTA
- preservatives e.g., sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate
- the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
- Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally-occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
- the emulsion may also contain sweetening and flavoring agents.
- Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
- sweetening agents such as glycerol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
- compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
- a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
- This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
- the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile fixed oils may conventionally be employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic
- a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight).
- the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
- an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
- Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
- the active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, and particularly about 1.5% w/w.
- Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
- Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
- Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
- Suitable formulations include aqueous or oily solutions of the active ingredient.
- Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of Pneumovirinae infections as described below.
- the invention is a novel, efficacious, safe, nonirritating and physiologically compatible inhalable composition
- a compound disclosed herein, or a pharmaceutically acceptable salt thereof e.g., a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof
- Preferred pharmaceutically acceptable salts are inorganic acid salts including hydrochloride, hydrobromide, sulfate or phosphate salts as they may cause less pulmonary irritation.
- the inhalable formulation is delivered to the endobronchial space in an aerosol comprising particles with a mass median aerodynamic diameter (MMAD) between about 1 and about 5 ⁇ m.
- MMAD mass median aerodynamic diameter
- the compound disclosed herein, or a pharmaceutically acceptable salt thereof e.g., a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof
- pMDI pressurized metered dose inhaler
- DPI dry powder inhaler
- Non-limiting examples of nebulizers include atomizing, jet, ultrasonic, pressurized, vibrating porous plate, or equivalent nebulizers including those nebulizers utilizing adaptive aerosol delivery technology ( Denyer, J. Aerosol medicine Pulmonary Drug Delivery 2010, 23 Supp 1, S1-S10 ).
- a jet nebulizer utilizes air pressure to break a liquid solution into aerosol droplets.
- An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets.
- a pressurized nebulization system forces solution under pressure through small pores to generate aerosol droplets.
- a vibrating porous plate device utilizes rapid vibration to shear a stream of liquid into appropriate droplet sizes.
- the formulation for nebulization is delivered to the endobronchial space in an aerosol comprising particles with a MMAD predominantly between about 1 ⁇ m and about 5 ⁇ m using a nebulizer able to aerosolize the formulation of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof) into particles of the required MMAD.
- a pharmaceutically acceptable salt thereof e.g., a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof
- the majority of aerosolized particles should not have a MMAD greater than about 5 ⁇ m.
- an aerosol contains a large number of particles with a MMAD larger than 5 ⁇ m, the particles are deposited in the upper airways decreasing the amount of drug delivered to the site of inflammation and bronchoconstriction in the lower respiratory tract. If the MMAD of the aerosol is smaller than about 1 ⁇ m, then the particles have a tendency to remain suspended in the inhaled air and are subsequently exhaled during expiration.
- the aerosol formulation for nebulization delivers a therapeutically efficacious dose of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof) to the site of Pneumovirinae infection sufficient to treat the Pneumovirinae infection.
- the amount of drug administered must be adjusted to reflect the efficiency of the delivery of a therapeutically efficacious dose of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
- a combination of the aqueous aerosol formulation with the atomizing, jet, pressurized, vibrating porous plate, or ultrasonic nebulizer permits, depending on the nebulizer, about, at least, 20, to about 90%, typically about 70% delivery of the administered dose of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof).
- a pharmaceutically acceptable salt thereof e.g., a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof.
- at least about 30 to about 50% of the active compound is delivered. More preferably, about 70 to about 90% of the active compound is delivered.
- a compound disclosed herein, or a pharmaceutically acceptable salt thereof is delivered as a dry inhalable powder.
- the compounds of the invention are administered endobronchially as a dry powder formulation to efficacious deliver fine particles of compound into the endobronchial space using dry powder or metered dose inhalers.
- the compound disclosed herein is processed into particles with, predominantly, MMAD between about 1 ⁇ m and about 5 ⁇ m by milling spray drying, critical fluid processing, or precipitation from solution.
- excipients are added to the compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof) before processing into particles of the required sizes.
- excipients are blended with the particles of the required size to aid in dispersion of the drug particles, for example by using lactose as an excipient.
- Particle size determinations are made using devices well known in the art.
- a multi-stage Anderson cascade impactor or other suitable method such as those specifically cited within the US Pharmacopoeia Chapter 601 as characterizing devices for aerosols within metered-dose and dry powder inhalers.
- compound disclosed herein, or a pharmaceutically acceptable salt thereof is delivered as a dry powder using a device such as a dry powder inhaler or other dry powder dispersion devices.
- Non-limiting examples of dry powder inhalers and devices include those disclosed in US5,458,135 ; US5,740,794 ; US5775320 ; US5,785,049 ; US3,906,950 ; US4,013,075 ; US4,069,819 ; US4,995,385 ; US5,522,385 ; US4,668,218 ; US4,667,668 ; US4,805,811 and US5,388,572 .
- One design is a metering device in which a reservoir for the drug is place within the device and the patient adds a dose of the drug into the inhalation chamber.
- the second design is a factory-metered device in which each individual dose has been manufactured in a separate container. Both systems depend on the formulation of the drug into small particles of MMAD from 1 ⁇ m and about 5 ⁇ m, and often involve co-formulation with larger excipient particles such as, but not limited to, lactose. Drug powder is placed in the inhalation chamber (either by device metering or by breakage of a factory-metered dosage) and the inspiratory flow of the patient accelerates the powder out of the device and into the oral cavity.
- Non-laminar flow characteristics of the powder path cause the excipient-drug aggregates to decompose, and the mass of the large excipient particles causes their impaction at the back of the throat, while the smaller drug particles are deposited deep in the lungs.
- compound disclosed herein, or a pharmaceutically acceptable salt thereof e.g., a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof
- compound disclosed herein, or a pharmaceutically acceptable salt thereof is delivered as a dry powder using a metered dose inhaler.
- metered dose inhalers and devices include those disclosed in US5,261,538 ; US5,544,647 ; US5,622,163 ; US4,955,371 ; US3,565,070 ; US3,361306 and US6,116,234 .
- a compound disclosed herein, or a pharmaceutically acceptable salt thereof is delivered as a dry powder using a metered dose inhaler wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of about 1-5 ⁇ m.
- Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- the formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
- sterile liquid carrier for example water for injection
- Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
- Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
- formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
- the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
- Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
- controlled release formulations in which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.
- Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day; typically, from about 0.01 to about 10 mg/kg body weight per day; more typically, from about .01 to about 5 mg/kg body weight per day; most typically, from about .05 to about 0.5 mg/kg body weight per day.
- the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.
- One or more compounds of the invention are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
- An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.
- compositions of the invention are also used in combination with other active ingredients.
- the other active therapeutic agent is active against Pneumovirinae virus infections, particularly respiratory syncytial virus infections.
- Non-limiting examples of these other active therapeutic agents are ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS-433771, ALN-RSV01, ALX-0171 and mixtures thereof.
- additional active therapeutics used to treat respiratory symptoms and sequelae of infection may be used in combination with the compounds disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof).
- the additional agents are preferably administered orally or by direct inhalation.
- other preferred additional therapeutic agents in combination with the compounds disclosed herein for the treatment of viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids.
- Glucocorticoids which were first introduced as an asthma therapy in 1950 ( Carryer, Journal of Allergy, 21, 282-287, 1950 ), remain the most potent and consistently effective therapy for this disease, although their mechanism of action is not yet fully understood ( Morris, J. Allergy Clin. Immunol., 75 (1 Pt) 1-13, 1985 ).
- oral glucocorticoid therapies are associated with profound undesirable side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, acceleration of cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Gilman, 10th edition, 2001).
- a solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation.
- corticosteroids Inhaled corticosteroids (ICS) have been developed to mitigate the severe adverse effects of oral steroids.
- Non-limiting examples of corticosteroids that may be used in combinations with the compound disclosed herein, or a pharmaceutically acceptable salt thereof are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisones, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone diproprionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocortin-21-butylate, flumethasone, flumeta
- anti-inflamatory agents working through anti-inflamatory cascade mechanisms are also useful as additional therapeutic agents in combination with the compounds disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., compounds of formula I or a pharmaceutically acceptable salt thereof or compound of formulas 1-103 or a pharmaceutically acceptable salt thereof) for the treatment of viral respiratory infections.
- a pharmaceutically acceptable salt thereof e.g., compounds of formula I or a pharmaceutically acceptable salt thereof or compound of formulas 1-103 or a pharmaceutically acceptable salt thereof
- anti-inflammatory signal transduction modulators like phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., blocking NF ⁇ B through IKK inhibition), or kinase inhibitors (e.g., blocking P38 MAP, JNK, PI3K, EGFR or Syk) is a logical approach to switching off inflammation as these small molecules target a limited number of common intracellular pathways - those signal transduction pathways that are critical points for the anti-inflammatory therapeutic intervention (see review by P.J. Barnes, 2006).
- phosphodiesterase inhibitors e.g., PDE-4, PDE-5, or PDE-7 specific
- transcription factor inhibitors e.g., blocking NF ⁇ B through IKK inhibition
- kinase inhibitors e.g., blocking P38 MAP, JNK, PI3K, EGFR or Syk
- non-limiting additional therapeutic agents include: 5-(2,4-Difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797); 3-Cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluorormethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-Dichloro-pyridin
- Combinations comprising inhaled ⁇ 2-adrenoreceptor agonist bronchodilators such as formoterol, albuterol or salmeterol with a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof) are also suitable, but non-limiting, combinations useful for the treatment of respiratory viral infections.
- a pharmaceutically acceptable salt thereof e.g., a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof
- Combinations of inhaled p2-adrenoreceptor agonist bronchodilators such as formoterol or salmeterol with ICS's are also used to treat both the bronchoconstriction and the inflammation (Symbicort® and Advair®, respectively).
- the combinations comprising these ICS and p2-adrenoreceptor agonist combinations along with the compounds disclosed herein are also suitable, but non-limiting, combinations useful for the treatment of respiratory viral infections.
- anticholinergics are of potential use and, therefore, useful as an additional therapeutic agents in combination with a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof) for the treatment of viral respiratory infections.
- a pharmaceutically acceptable salt thereof e.g., a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formulas 1-103 or a pharmaceutically acceptable salt thereof
- anticholinergics include, but are not limited to, antagonists of the muscarinic receptor (particularly of the M3 subtype) which have shown therapeutic efficacy in man for the control of cholinergic tone in COPD (Witek, 1999); 1- ⁇ 4-Hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)-propionyl]-pyrrolidine-2-carbonyl ⁇ -pyrrolidine-2-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide; 3-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonia-bicyclo[3.2.1]octane (Ipratropium-N,N-diethylglycinate); 1-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-
- the compounds of formula I or a compound of formulas 1-103 may also be combined with mucolytic agents to treat both the infection and symptoms of respiratory infections.
- a non-limiting example of a mucolytic agent is ambroxol.
- the compounds of formula I or the compounds of formulas 1-103 may be combined with expectorants to treat both the infection and symptoms of respiratory infections.
- a non-limiting example of an expectorant is guaifenesin.
- Nebulized hypertonic saline is used to improve immediate and long-term clearance of small airways in patients with lung diseases ( Kuzik, J. Pediatrics 2007, 266 ).
- the compounds of formula I or the compounds of formulas 1-103 may also be combined with nebulized hypertonic saline particularly when the Pneumovirinae virus infection is complicated with bronchiolitis.
- the combination of the compounds of formula I or the compounds of formulas 1-103 with hypertonic saline may also comprise any of the additional agents discussed above.
- nebulized about 3% hypertonic saline is used.
- any compound of the invention with one or more additional active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient.
- the combination therapy may be administered as a simultaneous or sequential regimen.
- the combination When administered sequentially, the combination may be administered in two or more administrations.
- Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are both present in the body of the patient.
- Co-administration includes administration of unit dosages of the compounds of the invention before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active therapeutic agents.
- a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents.
- a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes.
- a unit dose of a compound of the invention may be desirable to administer a unit dose of a compound of the invention first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the invention.
- the combination therapy may provide "synergy” and "synergistic", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
- a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
- a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections in separate syringes.
- an effective dosage of each active ingredient is administered sequentially, i.e. serially
- effective dosages of two or more active ingredients are administered together.
- a synergistic anti-viral effect denotes an antiviral effect which is greater than the predicted purely additive effects of the individual compounds of the combination.
- One embodiment provides for a compound of formula I or a compound of formulas 1-103, or a pharmaceutically acceptable salt, solvate, and/or ester thereof for use in methods of treating a Pneumovirinae virus infection (e.g., a Human respiratory syncytial virus infection) in a patient (e.g., a human).
- a Pneumovirinae virus infection e.g., a Human respiratory syncytial virus infection
- a patient e.g., a human.
- One embodiment provides for a compound of formula I or a compound of formulas 1-103, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent for use in methods of treating a Pneumovirinae virus infection in a patient (e.g., a human).
- One embodiment provides for a compound of formula I or a compound of formulas 1-103, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent for use in methods of treating Human respiratory syncytial virus infection in a patient (e.g., a human).
- the disclosure includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
- Such products typically are identified by preparing a radiolabelled (e.g. 14 C or 3 H) compound of the invention, administering it parenterally in a detectable dose (e.g.
- metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art.
- the conversion products so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no HSV antiviral activity of their own.
- compositions and methods for determining stability of compounds in surrogate gastrointestinal secretions are known.
- Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are deprotected in surrogate intestinal or gastric juice upon incubation for 1 hour at 37°C. Simply because the compounds are stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo.
- the prodrugs of the compounds of the invention typically will be stable in the digestive system but may be substantially hydrolyzed to the parental drug in the digestive lumen, liver, lung or other metabolic organ, or within cells in general.
- N -Boc-( S )-piperidine-2-carboxylic acid (5.0 g, 22 mmol) in DMF (100 mL) was treated with Cs 2 CO 3 (3.5 g, 10.9 mmol) and MeI (1.5 mL, 24 mmol). The mixture was stirred for 4 hours and diluted with MTBE (250 mL). The mixture was washed with water (twice with 100 mL) and saturated sodium chloride solution (100 mL).
- Intermediate 9 was separated by chiral SFC (see below) to give intermediate 9a (earlier eluting, 16.3 g ,41 %) and intermediate 9b (later eluting, 16.7 g , 41%) as white solids.
- HATU (1.37 g, 3.59 mmol) was added to a solution of 5-chloro-2-(methylsulfonamido)benzoic acid (823 mg, 3.29 mmol) in DMF (15.0 mL), and the reaction mixture was stirred at room temperature. After 1 h, a solution of crude intermediate 6 (220 mg, 2.99 mmol) in DMF (1 mL) was added followed by the addition of triethylamine (2.00 mL, 14.3 mmol), and the reaction mixture was stirred at room temperature for 19 h. The reaction mixture was partitioned between ethyl acetate (250 mL) and saturated aqueous sodium bicarbonate solution (200 mL), and the layers were separated.
- the intermediate 18 (0.3g, 0.867 mmol), and DMAP (0.117 g, 0.958 mmol) were dissolved in anhydrous pyridine (15 mL) and placed under nitrogen with stirring. POCl 3 (0.567ml, 6.07 mmol) was added neat and the reaction was heated to 100°C for 2 hours. The reaction was monitored by LC/MS. When it was complete in about 2 hours the reaction was cooled to room temperature and solvents were removed by rotary evaporation. The residue was redissolved in 200 ml DCM and washed with 200 ml water. The organic layer was collected dried over MgSO 4 (anhydrous), filtered and then evaporated.
- POCl 3 0.567ml, 6.07 mmol
- the starting intermediate 19 (0.06g, 0.165 mmol), along with sodium acetate (0.027 g, 0.330 mmol) were dissolved in absolute ethanol (10 mL). Solid Pd/C (5% by wt) (0.030g) was added and the reaction was placed under a balloon of hydrogen for 20 minutes. Catalyst was filtered off using a 40 micron syringe filter. The solvent was removed by rotary evaporation. The residue was taken up in DCM and loaded onto a silica gel column. The intermediate 20 was eluted with a 0 to 50% EtOAc in hexanes gradient. (Yield ⁇ 40 mg, 0.121 mmol, 73 %).
- the intermediate 23 (0.10g, 0.28 mmol), was dissolved in anhydrous 1,4-dioxane (6 ml). With stirring under nitrogen 4N HCl in dioxane (3 ml) was added via syringe. The reaction was stirred for 2 hours at room temperature while monitoring by LC/MS. When the reaction was complete the solvent was removed by rotary evaporation. The product, intermediate 24, was taken forward without further purification after it was characterized by LC/MS (Yield ⁇ 73 mg, 0.28 mmol, 100 %). LCMS m / z [M+H] + 261
- intermediate 38 was synthesized as a white solid (107 mg, 90%) after silica gel column chromatography (15-75% ethyl acetate in hexanes).
- Triphenylphosphine (87 mg, 0.332 mmol) was added to a solution of intermediate 38 (97 mg, 0.163 mmol) in 5 mL of THF at room temperature. After 90 minutes, 0.2 mL of water was added and mixture was heated at 60 °C overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (0-10% methanol in dichloromethane) to yield intermediate 39 (44 mg, 48%).
- N-chlorosuccinimide (239 mg, 1.79 mmol) was added to a solution of 4-fluoro-2-(methylsulfonamido)benzoic acid (351 mg, 1.51 mmol) in 9 mL of DMF at room temperature. After stirring overnight, mixture was poured into 90 mL of water and extracted three times with ethyl acetate.
- Example 60 Preparation of intermediate 61.
- Trifluoroacetic acid (0.070 mL, 0.831 mmol) was added to a solution of intermediate 64 (8 mg, 0.024 mmol) in 1 mL of CH 2 Cl 2 . After stirring overnight, LC/MS indicated full removal of Boc group. The reaction mixture was concentrated under reduced pressure and dried in-vacuo for two hours. To a solution of the resulting residue dissolved in 1.5 mL of anhydrous CH 2 Cl 2 was added 5-chloro-2-(methylsulfonamido)benzoyl chloride (6.5 mg, 0.0252 mmol).
- Triethylamine (0.35 mL, 2.51 mmol) was added to a mixture of intermediate 67 (109 mg, 0.226 mmol) and (S)-tert-butyl pyrrolidin-3-ylcarbamate (469 mg, 2.52 mmol) in 9 mL of anhydrous methanol. The mixture was heated at 75 °C overnight. Analytical HPLC indicated about 15% conversion to intermediate 68. Additional (S)-tert-butyl pyrrolidin-3-ylcarbamate (1.81 g) was added along with triethylamine (0.9 mL) and mixture was heated again for five days.
- preparatory HPLC 5-100% MeCN/H 2 O, 0.1% trifluoroacetic acid modifier
- Example 80 Preparation of intermediate 82.
- Example 84 Preparation of intermediate 86.
- Trifluoroacetic acid (1 mL, 12.9 mmol) was added to a solution of intermediate 66 (131 mg, 0.375 mmol) in 20 mL of dichloromethane at room temperature. After stirring overnight, the reaction mixture was concentrated under reduced pressure and dried in-vacuo for two hours. The resulting film was dissolved in 4 mL of methanol and (S)-tert-butyl pyrrolidin-3-ylcarbamate (710 mg, 3.82 mmol) and triethylamine (0.52 mL, 3.7 mmol) were added. Mixture was heated at 77 °C overnight. LC/MS indicated approximately 25% conversion to desired product.
- HATU 48 mg, 0.126 mmol was added to a solution of 5-methyl-3-(methylsulfonamido)thiophene-2-carboxylic acid (24 mg, 0.102 mmol) in 2 mL of anhydrous DMF at room temperature. After 90 minutes, a 0.5 mL acetonitrile solution of intermediate 87 (36 mg, 0.09 mmol) was added, followed by triethylamine (0.030 mL, 0.217 mmol). After stirring overnight, the reaction mixture was poured into a 1:1 solution of water and brine and extracted with ethyl acetate three times.
- Trifluoroacetic acid (0.070 mL, 0.831 mmol) was added to a solution of intermediate 64 (110 mg, 0.33 mmol) in 5 mL of CH 2 Cl 2 . After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure and the residue was purified by prep HPLC (15-100% Acetonitrile (with 0.1% trifluoroacetic acid) in water (with 0.1% trifluoroacetic acid)) to yield intermediate 90 (114 mg, 100%) as a solid, trifluoroacetic acid salt, after lyophilization.
- LCMS m/z [M+H] + C 11 H 13 ClN 4 requires: 237.08. Found 237.10. HPLC Tr (min), purity %: 1.36, 95%
- HATU 45mg, 0.12 mmol
- 6-Methyl-2-picolinic acid (12 mg, 0.09 mmol) were mixed in 2 mL of DMF and the reaction mixture was stirred for ten minutes before intermediate 90 (20 mg, 0.06 mmol) and triethylamine (33 ⁇ L, 0.24 mmol) were added to the solution.
- HATU 45mg, 0.12 mmol
- 2-methyl-5-chlorobenzoic acid 16 mg, 0.09 mmol
- intermediate 90 20 mg, 0.06 mmol
- triethylamine 33 ⁇ L, 0.24 mmol
- Example 100 Preparation of intermediate 102.
- Example 102 Preparation of intermediate 104.
- Example 103 Preparation of intermediate 105.
- Example 104 Preparation of intermediate 106.
- Example 106 Preparation of intermediate 108.
- N-chlorosuccinimide (528 mg, 3.95 mmol) was added to a solution of 5-fluoro-2-(methylsulfonamido)benzoic acid (705 mg, 3.03 mmol) in 9 mL of anhydrous DMF. After stirring overnight, the reaction mixture was poured into 100 mL of water and 50 mL of brine and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with 300 mL of 1:1 water:brine, dried (MgSO 4 ), filtered, and concentrated under reduced pressure to yield intermediate 109 (746 mg, 93%).
- Example 109 Preparation of intermediate 113.
- Example 111 Preparation of intermediate 115.
- Step 1 Sodium azide (158 mg, 2.43 mmol) was added to a solution of methyl 2-(bromomethyl)-5-chlorobenzoate (518 mg, 1.97 mmol) in 3 mL of DMF at room temperature. After stirring overnight, reaction mixture was quenched with 25 mL of water. The aqueous was extracted with ethyl acetate (3x30 mL) and the combined organics were washed with water (2x40 mL) and 50 mL of brine.
- Step 2 Lithium hydroxide monohydrate (794 mg, 18.9 mmol) was added to a solution of methyl 2-(azidomethyl)-5-chlorobenzoate (426 mg, 1.88 mmol), from the previous step, in 27 mL of 1:1:1 THF:methanol:water at room temperature. After stirring overnight, the reaction mixture was quenched with 20 mL of 2N HCl (aq) , and extracted with ethyl acetate (3x30 mL). The combined organics were washed with brine, dried (MgSO 4 ), filtered, and concentrated under reduced pressure to yield intermediate 115 (395 mg, 99%) as a white solid.
- intermediate 116 (1.33 g, 72%) was synthesized as a yellow solid.
- intermediate 12 (2640 mg, 6.59 mmol) and TEA (1.83 mL, 13.2 mmol) in DMF (8.8 mL).
- carboxylic acids ( B2 ) (between 0.10 mmol and 0.50 mmol) were placed in separate 2-ml vials. Then, into each vial was dispensed a solution of intermediate 12 (0.050 mmol) followed by the addition of HATU (38 mg, 0.10 mmol). The resulting reaction mixtures were stirred at room temperature for 16 h. Then, to each reaction mixture was added EtOAc (4 mL), washed with sat.
- Ethane-1,2-diamine (6.7 ⁇ L, 0.10 mmol) and sodium bicarbonate (16.0 mg, 0.20 mmol) were added to a solution of intermediate 33 (50 mg, 0.10 mmol) in acetonitrile (0.50 mL) and water (0.50 mL) and the reaction mixture was stirred at room temperature. After 12 h, azetidine hydrochloride (46.0 mg, 0.50 mmol) was added and the reaction mixture was stirred at 70 °C. After 5 h, the reaction mixture was allowed to cool to room temperature and was concentrated under reduced pressure.
- HATU 57 mg, 0.149 mmol was added to a solution of intermediate 96 (34 mg, 0.129 mmol) 1.2 mL of DMF at room temperature. After 60 minutes of stirring, intermediate 7 (22 mg, .067 mmol) was added followed immediately by triethylamine (0.023 mL, 0.168 mmol). Reaction mixture stirred at room temperature overnight under argon. Mixture was then poured into 30 mL of H 2 O and extracted three times with 30 mL of ethyl acetate.
- HATU 150 mg, 0.394 mmol was added to a solution of intermediate 99 (80 mg, 0.33 mmol) in 3.3 mL of DMF at room temperature. After 45 min of stirring, intermediate 12 (106 mg, 0.266 mmol) was added followed immediately by triethylamine (0.090 mL, 0.639 mmol). Reaction mixture stirred at room temperature overnight under argon. Mixture was then poured into 30 mL of H 2 O and extracted three times with 30 mL of ethyl acetate. The combined organic layers were washed with 50 mL brine, dried (MgSO 4 ), filtered, and concentrated under reduced pressure leaving a residue, which was dissolved in 7 mL of dichloromethane.
- Trifluoroacetic acid (0.7 mL, 8.9 mmol) was added and reaction mixture stirred at room temperature for 18 hours. Mixture was then concentrated under reduced pressure and purified by prep HPLC (15-100% Acetonitrile (with 0.1% trifluoroacetic acid) in water (with 0.1% trifluoroacetic acid)) to yield compound 27 (7.5 mg, 5%) as a white solid, trifluoroacetic acid salt, after lyophilization.
- LCMS m/z [M+H] + C 26 H 35 N 7 O 3 S requires: 526.25. Found 526.18. HPLC Tr (min), purity %: 4.87, 96%.
- reaction mixture was concentrated under reduced pressure and residue was purified by silica gel column chromatography (10-80% ethyl acetate in hexanes) to yield 27 mg of desired precursor, which was dissolved in 2 mL of dichloromethane and treated with trifluoroacetic acid (0.150 mL, 1.95 mmol). After stirring for one hour at room temperature, reaction mixture was concentrated under reduced pressure to yield compound 28 (26 mg, 17% over 3 steps), as an orange-yellow solid, trifluoroacetic acid salt.
- LCMS m/z [M+H] + C 26 H 35 N 7 O 3 S requires: 526.25. Found 526.19. HPLC Tr (min), purity %: 4.88, 97%.
- N-chlorosuccinimde 99.4 mg, 0.744 mmol was added to a solution of intermediate 108 (142 mg, 0.609 mmol) in 3.5 mL of DMF at room temperature. After stirring overnight, reaction mixture was poured into water and extracted three times with ethyl acetate. Combined organics were washed with water and brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure to yield 5-chloro-3-fluoro-2-(methylsulfonamido)benzoic acid (142 mg, 87%, 90% HPLC purity) which was used without further purification.
- HATU (87.4 mg, 0.230 mmol) was added to a solution of 5-chloro-3-fluoro-2-(methylsulfonamido)benzoic acid (55.1 mg, 0.206 mmol) in 5 mL of DMF at room temperature. After 45 minutes, a 0.5 M DMF solution of intermediate 26 (0.3 mL, 0.15 mmol) and triethylamine (0.050 mL, 0.375 mmol) were added. Reaction mixture stirred at room temperature overnight under argon. Mixture was then poured into 50 mL of H 2 O and extracted three times with 30 mL of ethyl acetate.
- Step 1 Triphenylphosphine (87 mg, 0.332 mmol) was added to a solution of intermediate 38 (97 mg, 0.163 mmol) in 5 mL of THF at room temperature. After 90 minutes, 0.2 mL of water was added and mixture was heated at 60 °C overnight. Reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (0-10% methanol in dichloromethane) to yield the intermediate benzylamine (44 mg, 48%).
- Step 2 Previous intermediate from step 1 was dissolved in 2 mL of dichloromethane and triethylamine (0.035 mL, 0.249 mmol) was added. Solution was cooled to 0°C and methane sulfonylchloride (0.020 mL, 0.238 mmol) was added. Reaction mixture was warmed to room temperature, stirred overnight, then concentrated under reduced pressure. Residue was purified by silica gel column chromatography (10-90% ethyl acetate in hexanes) to yield the intermediate benzylsulfonamide (35 mg, 78%).
- Step 3 Previous intermediate from step 2 (27 mg, 0.042 mmol) was dissolved in 1.5 mL of dichloromethane at room temperature. Trifluoroacetic acid (0.135 mL, 1.74 mmol) was added and reaction mixture stirred overnight. Reaction mixture was concentrated under reduced pressure to yield compound 36 (26 mg, 99%) as a white solid film, trifluoroacetic acid salt.
- Example 154 Preparation of compound 38 and compound 39.
- Triethylamine (0.100 mL, 0.717 mmol) was added to a mixture of intermediate 11 (71 mg, 0.147 mmol) and tert-butyl 1,6-diazaspiro[3.3]heptane-6-carboxylate (114 mg, 0.575 mmol) in 5 mL of methanol at room temperature. After heating at 75 °C overnight, reaction mixture was cooled to room temperature and concentrated under reduced pressure.
- Example 172 Preparation of compound 57.
- Example 178 Preparation of compound 63.
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Claims (23)
- Composé de formule I :
dans lequel :a) Y1 est N, NH ou CH, Y2 est C, Y3 est N ou CR8', Y4 est N ou C et Y5 est N, NR2' ou CR2, dans lequel au moins deux parmi Y1, Y2, Y3, Y4 et Y5 sont indépendamment N, NH ou NR2' ; oub) Y1 est N, NH ou CH, Y2 est N ou C, Y3 est N ou CR8, Y4 est N ou C, et Y5 est N ou NR2', dans lequel au moins deux parmi Y1, Y2, Y3, Y4 et Y5 sont indépendamment N, NH ou NR2' ; ouc) Y1 est N, NH ou CH, Y2 est N ou C, Y3 est CR8', Y4 est N ou C, et Y5 est N, NR2' ou CR2, dans lequel au moins deux parmi Y1, Y2, Y3, Y4 et Y5 sont indépendamment N, NH ou NR2' ;les traits pointillés - sont choisis parmi des simples liaisons et des doubles liaisons de façon à obtenir un système de cycle aromatique ;A est -(CR4R4')n- dans lequel un CR4R4' quelconque dudit -(CR4R4')n- peut être facultativement remplacé par -O-, -S-, ou -S(O)P- ;n est 3, 4, 5 ou 6 ;chaque p est 1 ou 2 ;Ar est un groupe hétérocyclyle en C2-C20 ou un groupe aryle en C6-C20, dans lequel le groupe hétérocyclyle en C2-C20 ou le groupe aryle en C6-C20 est facultativement substitué par 1 à 5 R6 ;X est -C(R13)(R14)-, -N(CH2R14)- ou -NH-, ou X est absent ;R1 est H, -OR11, -NR11R12, -NR11C(O)R11, -NR11C(O)OR11, -NR11C(O)NR11R12, N3, CN, NO2, -SR11, -S(O)PRa, NR1]S(O)PRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)P(OR11), -SO2NR11R12, -NR11S(O)P(OR11), -NR11SOpNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;R2 est H, CN, NO2, halogène ou alkyle en C1-C8 ;R2' est H ou alkyle en C1-C8 ;R3 est H, -OR11, -NR11R12, -NR11C(O)R11, -NR11C(O)OR11, -NR11C(O)NR11R12, N3, CN, NO2, -SR11, -S(O)PRa, -NR11S(O)pRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)P(OR11), -SO2NR11R12, -NR11S(O)P(OR11), -NR11SOPNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;R3 est H, -OR11, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;chaque R4 est indépendamment H, -OR11, -NR11R12, -NR11C(O)OR11, -NR11C(O)NR11R12, N3, CN, NO2, -SR11, -S(O)PRa, -NR11S(O)pRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O) SR11, -S(O)P(OR11), -SO2NR11R12, -NR11S(O)P(OR11), -NR11SOPNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ; et chaque R4' est indépendamment H, OR11, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;ou deux R4 sur des atomes de carbone adjacents, lorsqu'ils sont assemblés conjointement, peuvent former une double liaison entre les deux carbones auxquels ils sont liés ou peuvent former un cycle cycloalkyle en C3-C7 dans lequel un atome de carbone dudit cycle cycloalkyle en C3-C7 peut être facultativement remplacé par -O-, -S-, -S(O)p-, -NH- ou -NRa- ;ou deux R4 sur des atomes de carbone non adjacents, lorsqu'ils sont assemblés conjointement, peuvent former un cycle cycloalkyle en C3-C7 dans lequel un atome de carbone dudit cycle cycloalkyle en C3-C7 peut être facultativement remplacé par -O-, -S-, -S(O)P-, -NH- ou -NRa- ;ou deux R4 et deux R4' sur des atomes de carbone s, lorsqu'ils sont assemblés conjointement, peuvent former un cycle aryle en C6 facultativement substitué ;ou un R4 et un R4' sur le même atome de carbone, lorsqu'ils sont assemblés conjointement, peuvent former un cycle cycloalkyle en C3-C7 dans lequel un atome de carbone dudit cycloalkyle en C3-C7 peut être facultativement remplacé par -O-, -S-, -S(O)P-, -NH- ou -NRa- ;chaque R5 est indépendamment H, -OR11, -NR11R12, -NR11C(O)OR11, -NR11C(O)NR11R12, N3, CN, NO2, -SR11, -S(O)PRa, -NR11S(O)pRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)P(OR11), -SO2NR11R12, -NR11S(O)P(OR11), -NR11SOPNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;chaque R5' est indépendamment H, -OR11, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;chaque R6 est indépendamment H, oxo, -OR11, -NR11R12, -NR11C(O)R11, -NR11C(O)OR11, -NR11C(O)N R11R12, N3, CN, NO2, -SR11, -S(O)pRa, -NR11S(O)PRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)p(OR11), -SO2NR1 1R12, -NR11S(O)P(OR11), -NR11SOPNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;ou deux R6 sur des atomes de carbone adjacents, lorsqu'ils sont assemblés conjointement, peuvent former un cycle cycloalkyle en C3-C7, dans lequel un atome de carbone dudit cycle cycloalkyle en C3-C7 peut être facultativement remplacé par -O-, -S-, -S(O)p-, -NH- ou -NRa- ;ou un R6 quelconque adjacent au groupe carbonyle associé dudit Ar, conjointement avec R3, peut former une liaison ou un groupe -(CR5R5')m- dans lequel m est 1 ou 2 ;ou un R6 quelconque adjacent au groupe carbonyle associé dudit Ar, conjointement avec R2 ou R2', peut former une liaison ;R7 est H, -OR11, -NR11R12, -NR11C(O)R11, -NR11C(O)OR11, -NR11C(O)NR11R12, N3, CN, NO2, -SR11, -S(O)pRa, -NR11S(O)PRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)P(OR11), -SO2NR11R12, -NR11S(O)P(OR11), -NR11SOPNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;R8 est H, -OR11, -NR11R12, -NR11C(O)R11, -NR11C(O)OR11, -NR11C(O)NR11R12, N3, CN, NO2, -SR11, -S(O)pRa, -NR11S(O)PRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)p(OR11), -SO2NR11R12, -NR11S(O)P(OR11), -NR11SOPNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;R8' est H, -OR11, -NR11R12, -NR11C(O)R11, -NR11C(O)OR11, -NR11C(O)NR11R12, N3, CN, NO2, -SR11, -S(O)pRa, -NR11S(O)PRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)p(OR11), -SO2NR11R12, -NR11S(O)P(OR11), -NR11SOPNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;chaque Ra est indépendamment alkyle en C1-C8, halogénoalkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8), dans lequel l'un quelconque des alkyle en C1-C8, halogénoalkyle en C1-C8, alcényle en C2-C8 ou alcynyle en C2-C8 de Ra est facultativement substitué par un ou plusieurs OH, NH2, CO2H, hétérocyclyle en C2-C20, et dans lequel l'un quelconque des aryl(alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) de Ra est facultativement substitué par un ou plusieurs -OH, -NH2, CO2H, hétérocyclyle en C2-C20 ou alkyle en C1-C8 ;chaque R11 ou R12 est indépendamment H, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, cycloalkyle en C3-C7, (cycloalkyle en C3-C7)-(alkyle en C1-C8), -C(=O)Ra ou -S(O)pRa ; ou lorsque R11 et R12 sont liés à un azote, ils peuvent facultativement être assemblés conjointement avec l'azote auquel ils sont tous deux liés pour former un cycle hétérocyclique de 3 à 7 chaînons, dans lequel un atome de carbone quelconque dudit cycle hétérocyclique peut facultativement être remplacé par -O-, -S-, -S(O)P-, -NH-, -NRa- ou -C(O)- ;R13 est H ou alkyle en C1-C8 ;R14 est H, alkyle en C1-C8, NR11R12, NR11C(O)R11, NR11C(O)OR11, NR11C(O)NR11R12, NR11S(O)pRa, -NR11S(O)P(OR11) ou NR11SOPNR11R12 ; etdans lequel chaque alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) de chaque R1, R2, R2', R3, R3', R4, R4', R5, R5', R6, R7, R8, R8', R11 ou R12 est indépendamment, facultativement substitué par un ou plusieurs oxo, halogène, hydroxy, -NH2, CN, N3, -N(Ra)2, -NHRa, -SH, -SRa, -S(O)PRa, -ORa, alkyle en C1-C8, halogénoalkyle en C1-C8, -C(O)Ra, -C(O)H, -C(=O)ORa, -C(=O)OH, -C(=O)N(Ra)2, -C(=O)NHRa, -C(=O)NH2, -NHS(O)pRa, -NRaS(O)pRa, -NHC(O)Ra, -NRaC(O)Ra, -NHC(O)ORa, -NRaC(O)ORa, -NRaC(O)NHRa, -NRaC(O)N(Ra)2, -NRaC(O)NH2, -NHC(O)NHRa, -NHC(O)N(Ra)2, -NHC(O)NH2, =NH, =NOH, =NORa, -NRaS(O)pNHRa, -NRaS(O)pN(Ra)2, -NRaS(O)PNH2, -NHS(O)PNHRa, -NHS(O)PN(Ra)2, -NHS(O)PNH2, -OC(=O)Ra, -OP(O)(OH)2 ou Ra. - Composé selon la revendication 1, dans lequel :a) Y1 est N, NH ou CH, Y2 est C, Y3 est N ou CR8', Y4 est N ou C et Y5 est N, NR2 ou CR2, dans lequel au moins deux parmi Y1, Y2, Y3, Y4 et Y5 sont indépendamment N, NH ou NR2' ; oub) Y1 est N, NH ou CH, Y2 est N ou C, Y3 est N ou CR8', Y4 est N ou C, et Y5 est N ou NR2', dans lequel au moins deux parmi Y1, Y2, Y3, Y4 et Y5 sont indépendamment N, NH ou NR2' ; ouc) Y1 est N, NH ou CH, Y2 est N ou C, Y3 est CR8', Y4 est N ou C, et Y5 est N, NR2 ou CR2, dans lequel au moins deux parmi Y1, Y2, Y3, Y4 et Y5 sont indépendamment N, NH ou NR2' ;les traits pointillés ---- sont choisis parmi des simples liaisons et des doubles liaisons de façon à obtenir un système de cycle aromatique ;A est -(CR4R4')n- dans lequel un CR4R4' quelconque parmi ledit -(CR4R4')n- peut être facultativement remplacé par -O-, -S-, ou -S(O)P- ;n est 3, 4, 5 ou 6 ;chaque p est 1 ou 2 ;Ar est un groupe hétérocyclyle en C2-C20 ou un groupe aryle en C6-C20, dans lequel le groupe hétérocyclyle en C2-C20 ou le groupe aryle en C6-C20 est facultativement substitué par 1 à 5 R6 ;X est -C(R13)(R14)-, -N(CH2R14)- ou -NH-, ou X est absent ;R1 est H, -OR11, -NR11R12, -NR11C(O)R11, -NR11C(O)OR11, -NR11C(O)NR11R12, N3, CN, NO2, -SR11, -S(O)pRa, -NR11S(O)PRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)p(OR11), -SO2NR11R12, -NR11S(O)P(OR11), -NR11SOPNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;R2 est H, CN, NO2, halogène ou alkyle en C1-C8 ;R2' est H ou alkyle en C1-C8 ;R3 est H, -OR11, -NR11R12, -NR11C(O)R11, -NR11C(O)OR11, -NR11C(O)NR11R12, N3, CN, NO2, -SR11, -S(O)pRa, -NR11S(O)PRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)p(OR11), -SO2NR11R12, -NR11S(O)P(OR11), -NR11SOPNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;R3' est H, -OR11, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;chaque R4 est indépendamment H, -OR11, -NR11R12, -NR11C(O)R11, -NR11C(O)OR11, -NR11C(O)NR11R12, N3, CN, NO2, -SR11, -S(O)pRa, -NR11S(O)PRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)p(OR11), -SO2NR11R12, -NR11S(O)P(OR11), -NR11SOPNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ; etchaque R4' est indépendamment H, OR11, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;chaque R6 est indépendamment H, oxo, -OR11, -NR11R12, -NR11C(O)R11, -NR11C(O)OR11, -NR11C(O)NR11R12, N3, CN, NO2, -SR11, -S(O)pRa, -NR11S(O)PRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)p(OR11), -SO2NR11R12, -NR11S(O)P(OR11), -NR11SOPNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;R7 est H, -OR11, -NR11R12, -NR11C(O)R11, -NR11C(O)OR11, -NR11C(O)NR11R12, N3, CN, NO2, -SR11, -S(O)pRa, -NR11S(O)PRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)p(OR11), -SO2NR11R12, -NR11S(O)P(OR11), -NR11SOPNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;R8 est H, -OR11, -NR11R12, -NR11C(O)R11, -NR11C(O)OR11, -NR11C(O)NR11R12, N3, CN, NO2, -SR11, -S(O)pRa, -NR11S(O)PRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)p(OR11), -SO2NR11R12, -NR11S(O)P(OR11), -NR11SOPNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;R8' est H, -OR11, , -NR11R12, -NR11C(O)R11, -NR11C(O)OR11, -NR11C(O)NR11R12, N3, CN, NO2, -SR11, -S(O)pRa, -NR11S(O)PRa, -C(=O)R11, -C(=O)OR11, -C(=O)NR11R12, -C(=O)SR11, -S(O)p(OR11), -SO2NR11R12, -NR11S(O)P(OR11), -NR11SOPNR11R12, -NR11C(=NR11)NR11R12, halogène, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) ;chaque Ra est indépendamment alkyle en C1-C8, halogénoalkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20)-(alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8), dans lequel l'un quelconque des alkyle en C1-C8, halogénoalkyle en C1-C8, alcényle en C2-C8 ou alcynyle en C2-C8 de Ra est facultativement substitué par un ou plusieurs OH, NH2, CO2H, hétérocyclyle en C2-C20, et dans lequel l'un quelconque des aryl(alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) de Ra est facultativement substitué par un ou plusieurs -OH, -NH2, CO2H, hétérocyclyle en C2-C20 ou alkyle en C1-C8 ;chaque R11 ou R12 est indépendamment H, alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, cycloalkyle en C3-C7, (cycloalkyle en C3-C7)-(alkyle en C1-C8), -C(=O)Ra ou -S(O)pRa ; ou lorsque R11 et R12 sont liés à un azote, ils peuvent facultativement être assemblés conjointement avec l'azote auquel ils sont tous deux liés pour former un cycle hétérocyclique de 3 à 7 chaînons dans lequel un atome de carbone quelconque dudit cycle hétérocyclique peut facultativement être remplacé par -O-, -S-, -S(O)P-, -NH-, -NRa- ou -C(O)- ;R13 est H ou alkyle en C1-C8 ;R14 est H, alkyle en C1-C8, NR11R12, NR11C(O)R11, NR11C(O)OR11, NR11C(O)NR11R12, NR11S(O)pRa, -NR11S(O)P(OR11) ou NR11SOPNR11R12 ; etdans lequel chaque alkyle en C1-C8, alcényle en C2-C8, alcynyle en C2-C8, aryl (alkyle en C1-C8), aryle en C6-C20, hétérocyclyle en C2-C20, (hétérocyclyle en C2-C20) - (alkyle en C1-C8), cycloalkyle en C3-C7 ou (cycloalkyle en C3-C7)-(alkyle en C1-C8) de chaque R1, R2, R2', R3, R3', R4, R4', R5, R5', R6, R7, R8, R8', R11 ou R12 est indépendamment, facultativement substitué par un ou plusieurs oxo, halogène, hydroxy, -NH2, CN, N3, -N(Ra)2, -NHRa, -SH, -SRa, -S(O)PRa, -ORa, alkyle en C1-C8, halogénoalkyle en C1-C8, -C(O)Ra, -C(O)H, -C(=O)ORa, -C(=O)OH, -C(=O)N(Ra)2, -C(=O)NHRa, -C(=O)NH2, -NHS(O)pRa, -NRaS(O)pRa, -NHC(O)Ra, -NRaC(O)Ra, -NHC(O)ORa, -NRaC(O)ORa, -NRaC(O)NHRa, -NRaC(O)N(Ra)2, -NRaC(O)NH2, -NHC(O)NHRa, -NHC(O)N(Ra)2, -NHC(O)NH2, =NH, =NOH, =NORa, -NRaS(O)pNHRa, -NRaS(O)pN(Ra)2, -NRaS(O)PNH2, -NHS(O)PNHRa, -NHS(O)PN(Ra)2 , -NHS(O)PNH2, -OC(=O)Ra, -OP(O)(OH)2 ou Ra.
- Composé selon l'une quelconque des revendications 1 à 3, dans lequel R3 et R3' sont chacun H.
- Composé selon l'une quelconque des revendications 1 à 4, dans lequel n est 3.
- Composé selon l'une quelconque des revendications 1 à 5, dans lequel chaque R4 et chaque R4' est H.
- Composé selon l'une quelconque des revendications 1 à 6, dans lequel A est -(CH2)3-.
- Composé selon l'une quelconque des revendications 1 à 7, dans lequela) Y1 est N, NH ou CH, Y2 est C, Y3 est N, Y4 est N ou C et Y5 est NR2' ou CR2, dans lequel au moins deux parmi Y1, Y2, Y3, Y4 et Y5 sont indépendamment N, NH ou NR2 ; oub) Y1 est N, NH ou CH, Y2 est N ou C, Y3 est N ou CR8', Y4 est N ou C, et Y5 est N, dans lequel au moins deux parmi Y1, Y2, Y3, Y4 et Y5 sont indépendamment N ou NH ; ouc) Y1 est N, NH ou CH, Y2 est N ou C, Y3 est CR8', Y4 est N ou C, et Y5 est NR2' ou CR2, dans lequel au moins deux parmi Y1, Y2, Y3, Y4 et Y5 sont indépendamment N, NH ou NR2 ;
oud) Y1 est N, Y2 est C, Y3 est N, Y4 est N et Y5 est CR2 ; oue) Y1 est N, Y2 est N, Y3 est CR8', Y4 est C, et Y5 est CR2. - Composé selon l'une quelconque des revendications 1 à 8, dans lequel R2', R2 et R8 sont chacun H.
- Composé selon la revendication 10, selon la formule Im dans lequel R2 est H.
- Composé selon l'une quelconque des revendications 1 à 9, ou composé selon la formule Im de la revendication 10, ou composé selon la revendication 11, dans lequel X est -C(R13)(R14)- ou X est absent.
- Composé selon l'une quelconque des revendications 1 à 9, ou composé selon la formule Im de la revendication 10, ou composé selon la revendication 11, dans lequel R13 est H et R14 est -NHS(O)2(alkyle en C1-C3).
- Composé selon l'une quelconque des revendications 1 à 9, ou composé selon la formule Im de la revendication 10, ou composé selon la revendication 11, dans lequel X est absent.
- Composé selon l'une quelconque des revendications 1 à 14, dans lequel R7 est H ou alkyle en C1-C8, dans lequel alkyle en C1-C8 est facultativement substitué par un ou plusieurs oxo, halogène, hydroxy, -NH2, CN, N3, -N(Ra)2, -NHRa, -SH, -SRa, S(O)PRa, -ORa, alkyle en C1-C8, halogénoalkyle en C1-C8, -C(O)Ra, -C(O)H, -C(=O)ORa, -C(=O)OH, -C(=O)N(Ra)2 , -C(=O)NHRa, -C(=O)NH2, -NHS(O)pRa, -NRaS(O)pRa, -NHC(O)R a, -NRaC(O)Ra, -NHC(O)ORa, -NRaC(O)ORa, -NRaC(O)NHRa, -NRa C(O)N(Ra)2, -NRaC(O)NH2, -NHC(O)NHRa, -NHC(O)N(Ra)2, -NHC( O)NH2, =NH, =NOH, =NORa, -NRaS(O)PNHRa, -NRaS(O)PN(Ra)2, -NRaS(O)PNH2, -NHS(O )PNHRa, -NHS(O)PN(Ra)2, -NHS(O)PNH2, -OC(=O)Ra, -OP(O)(OH)2 ou Ra,
par exemple, dans lequel R7 est H ou méthyle. - Composé selon l'une quelconque des revendications 1 à 15, dans lequel R1 est(a) H, -NR]1R12, alkyle en C1-C8 ou hétérocyclyle en C2-C20 dans lequel alkyle en C1-C8 ou hétérocyclyle en C2-C20 est facultativement substitué par un ou plusieurs oxo, halogène, hydroxy, -NH2, CN, N3, -N(Ra)2, -NHRa, -SH, -SRa, S(O)PRa, -ORa, alkyle en C1-C8, halogénoalkyle en C1-C8, -C(O)Ra, -C(O)H, -C(=O)ORa, -C(=O)OH, -C(=O)N(Ra)2 , -C(=O)NHRa, -C(=O)NH2, -NHS(O)pRa, -NRaS(O)pRa, -NHC(O)R a, -NRaC(O)Ra, -NHC(O)ORa, -NRaC(O)ORa, -NRaC(O)NHRa, -NRa C(O)N(Ra)2, -NRaC(O)NH2, -NHC(O)NHRa, -NHC(O)N(Ra)2, -NHC( O)NH2, =NH, =NOH, =NORa, -NRaS(O)PNHRa, -NRaS(O)PN(Ra)2, -NRaS(O)PNH2, -NHS(O )PNHRa, -NHS(O)PN(Ra)2, -NHS(O)PNH2, -OC(=O)Ra, -OP(O)(OH)2 ou Ra,
ou dans lequel(b) R1 est H, alkyle en C1-C3 ou -NR11R12, dans lequel chaque R11 ou R12 est indépendamment H ou alkyle en C1-C3 ; ou R11 et R12, conjointement avec l'azote auquel ils sont tous deux liés pour former un cycle hétérocyclique de 3 à 7 chaînons dans lequel un atome de carbone quelconque dudit cycle hétérocyclique peut facultativement être remplacé par -O-, -S-, -S(O)P-, -NH-, -NRa- ou -C(O)- ; ou dans lequel(c) R1 est H, méthyle ou azétidinyle. - Composé selon l'une quelconque des revendications 1 à 16, dans lequel(a) R8 est -NR11R12, alkyle en C1-C8 ou hétérocyclyle en C2-C20 dans lequel alkyle en C1-C8 ou hétérocyclyle en C2-C20 est facultativement substitué par un ou plusieurs oxo, halogène, hydroxy, -NH2, CN, N3, -N(Ra)2, -NHRa, -SH, -SRa, -S(O)PRa, -ORa, alkyle en C1-C8, halogénoalkyle en C1-C8, -C(O)Ra, -C(O)H, -C(=O)ORa, -C(=O)OH, -C(=O)N(Ra)2, -C(=O)NHRa, -C(=O)NH2, -NHS(O)PRa, -NRaS(O)pRa, -NHC(O)Ra, -NRaC(O)Ra, -NHC(O)ORa, -NRaC(O)ORa, -NRaC(O)NHRa, -NRaC(O)N(Ra)2, -NRaC(O)NH2, -NHC(O)NHRa, -NHC(O)N(Ra)2, -NHC(O)NH2, =NH, =NOH, =NORa, -NRaS(O)pNHRa, -NRaS(O)PN(Ra)2, -NRaS(O)PNH2, -NHS(O )pNHRa, -NHS(O)PN(Ra)2, -NHS(O)PNH2, -OC(=O)Ra, -OP(O)(OH)2 ou Ra ;
ou dans lequel(b) R8 est alkyle en C1-C8, azétidinyle ou pyrrolidinyle, dans lequel azétidinyle ou pyrrolidinyle est facultativement substitué par un ou plusieurs oxo, halogène, hydroxy, -NH2, CN, N3, -N(Ra)2, -NHRa, -SH, -SRa, -S(O)PRa, -ORa, alkyle en C1-C8, halogénoalkyle en C1-C8, -C(O)Ra, -C(O)H, -C(=O)ORa, -C(=O)OH, -C(=O)N(Ra)2 , -C(=O)NHRa, -C(=O)NH2, -NHS(O)pRa, -NRaS(O)PRa, -NHC(O)R a, -NRaC(O)Ra, -NHC(O)ORa, -NRaC(O)ORa, -NRaC(O)NHRa, -NRa C(O)N(Ra)2, -NRaC(O)NH2, -NHC(O)NHRa, -NHC(O)N(Ra)2, -NHC( O)NH2, =NH, =NOH, =NORa, -NRaS(O)PNHRa, -NRaS(O)PN(Ra)2, -NRaS(O)PNH2, -NHS(O)pNHRa, -NHS(O)PN(Ra)2, -NHS(O)PNH2, -OC(=O)Ra, -OP(O)(OH)2 ou Ra ;
ou dans lequel(c) R8 est méthyle, azétidinyle ou pyrrolidinyle, dans lequel azétidinyle ou pyrrolidinyle est facultativement substitué par un ou plusieurs hydroxy, NH2 ou CN. - Composé selon l'une quelconque des revendications 1 à 17, dans lequel(a) Ar est un phényle ou hétéroaryle monocyclique de 5 à 6 chaînons, dans lequel le phényle ou hétéroaryle monocyclique de 5 à 6 chaînons est facultativement substitué par 1 à 5 R6 ;
ou dans lequel(b) Ar est un phényle, pyridinyle ou thiényle, dans lequel phényle, pyridinyle ou thiényle est facultativement substitué par 1 à 5 R6. - Composé selon l'une quelconque des revendications 1 à 18, dans lequel(a) chaque R6 est -NR11S(O)pRa, halogène, ou alkyle en C1-C8 ;
ou dans lequel(b) chaque R6 est -NHS(O)2CH3, chloro, bromo ou méthyle. - Composition pharmaceutique comprenant une quantité thérapeutiquement efficace d'un composé comme décrit dans l'une quelconque des revendications 1 à 20 ou un sel pharmaceutiquement acceptable de celui-ci et un véhicule pharmaceutiquement acceptable,
la composition pharmaceutique comprenant facultativement en outre au moins un agent thérapeutique choisi parmi la ribavirine, le palivizumab, le motavizumab, RSV-IGIV, MEDI-557, A-60444, MDT-637, BMS-433771, ALN-RSV01 et ALX-0171 et des mélanges de ceux-ci. - Composé tel que décrit dans l'une quelconque des revendications 1 à 20, ou sel pharmaceutiquement acceptable de celui-ci, pour utilisation en thérapie médicale, par exemple pour utilisation dans le traitement thérapeutique ou prophylactique d'une infection par un virus Pneumovirinae ou une infection par le virus respiratoire syncytial.
- Composé pour utilisation selon la revendication 22, qui comprend en outre l'administration d'une quantité thérapeutiquement efficace d'au moins un autre agent thérapeutique ou une composition de celui-ci choisi dans le groupe constitué de la ribavirine, le palivizumab, le motavizumab, RSV-IGIV, MEDI-557, A-60444, MDT-63, BMS-433771, ALN-RSV01 et ALX-0171 et des mélanges de ceux-ci.
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